Zhengzhou, China

Zhengzhou University

www.zzu.edu.cn/
Zhengzhou, China

Zhengzhou University , colloquially known in Chinese as Zhèngdà is a public university located in Zhengzhou, Henan, People's Republic of China.It has the largest area of any university in China at 4,328,688 square meters. Wikipedia.


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News Article | May 17, 2017
Site: www.sciencedaily.com

Type 2 diabetes, a prolific killer, is on a steep ascent. According to the World Health Organization, the incidence of the condition has grown dramatically from 108 million cases in 1980 to well over 400 million today. The complex disease occurs when the body's delicate regulation of glucose, a critical metabolite, is disrupted, creating a condition of elevated blood sugar known hyperglycemia. Over time, the condition can damage the heart, blood vessels, eyes, kidneys, and nerves. In a new study, Wei Liu and his colleagues at The Biodesign Institute join an international team, led by Beili Wu from the Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, to explore a central component in glucose regulation. Their findings shed new light on the structure of the glucagon receptor, a highly promising target for diabetes drug development. "The biggest highlight of this paper is that we now have a full-length structure of a class B GPCR," Liu says, referring to a specialized cell-surface receptor able to bind with signaling molecules and influence blood sugar regulation. In addition to ASU, scientists at SIMM, in collaboration with several groups based in China (ShanghaiTech University, Zhengzhou University and Fudan University), United States (University of Southern California, The Scripps Research Institute, and GPCR Consortium), the Netherlands (Vrije Universiteit Amsterdam) and Denmark (Novo Nordisk), provided a detailed molecular map of the full-length human glucagon receptor (GCGR) in complex with a modulator (NNC0640) and the antigen-binding antibody fragment (mAb1). The research appears in the advanced online edition of the journal Nature. GPCRs (for G-Protein Coupled Receptors) are specialized receptors adorning cell surfaces. They act like email inboxes for important messages, which arrive at the outer membrane in the form of binding molecules or ligands that affect cell behavior and regulation. Receptor-ligand binding alters the conformation of the receptor and sends messages to the cell's interior, guiding cell function. Pharmaceutical companies hope to develop new drugs that can more accurately and efficiently bind with cell receptors, including diabetes drugs that will be able to halt or reduce the overproduction of glucose. The detailed structure of the glucagon receptor (or "GCGR") examined in the study was solved using the technique of X-ray crystallography. Here, a crystallized protein is struck with X-rays, which form a diffraction pattern that can be reassembled into an extremely detailed picture of the sample. Such information is vital for the development of effective drugs, which must bind with their complex target cell receptors with great specificity. Binding of a specific ligand to the glucagon receptor triggers the release of glucose from the liver during fasting, making this receptor a critical component for maintaining normal glucose levels in the body. Class B GPCRs are essential to numerous physiological processes and serve as important drug targets for many human diseases such as type 2 diabetes, metabolic syndrome, osteoporosis, migraine, depression and anxiety. According to team leader and SIMM professor Dr. Beili Wu, "The GCGR structure provides a clear picture of a full-length class B GPCR at high resolution, and helps us understand how different domains cooperate in modulating the receptor function at the molecular level." The GCGR receptor consists of three key components: an extracellular domain (ECD), which protrudes above the surface of the cell, a transmembrane domain (TCD), which is anchored into the cell membrane itself and a region known as the stalk, which connects the two domains and acts as a kind of pivot. (Figure 1 shows the basic structure of the GCGR receptor made up of an extracellular domain, stalk region and transmembrane region. Also pictured is the binding antibody mAb23.) The results of the new study are significant because all three parts of the receptor are essential for its ability to properly bind with its target molecules."Previously we had solved the structure for this GPCR, but we had truncated the whole extracellular domain, which is a critical part for ligand binding," Liu says. Further, although the stalk region contains just 12 amino acids, it is critical for activating and de-activating the GCGR receptor. Progressive diabetes can result in serious health complications, including heart disease, blindness, kidney failure, and lower-extremity amputations. It is currently the seventh leading cause of death in the United States. Proper regulation of blood sugar levels relies on two key hormones, which together act like a kind of thermostat. When blood sugar becomes elevated above the normal threshold, insulin is produced by islet cells in the pancreas, acting to keep blood sugar in check. But an even greater risk to the body occurs should blood sugar fall dangerously low. Indeed, low blood sugar or hypoglycemia can be fatal as glucose is the most important brain metabolite, essential for survival. Under conditions of hypoglycemia, another hormone, known as glucagon is produced by pancreatic ?-cells. Glucagon acts as the main counter-regulatory hormone, opposing the action of insulin and switching on glucose production in the liver during fasting. Glucagon influences target tissues through activation of the GCGR receptor. In Type 2 diabetes, insulin production is impaired, leading to elevated blood sugar. Treatment for the disease with supplemental insulin has therefore been a therapy of choice for most patients of the disease. But diabetes also affects glucagon production through dysregulation of the GCGR receptor, causing the overproduction of glucose. The combination of insulin deficiency and glucose excess is typical of Type II diabetes and calls for a multi-pronged approach to addressing the disease. The idea of targeting the GCGR receptor with drugs able to bind with it and switch it off has long been proposed and experiments in rats indicate that the approach is sound. Much more work is required however to perform the same feat in humans. Now, with the complete structure of the receptor in hand, pharmaceutical companies are poised to develop much more effective drugs that specifically target glucose production, while avoiding undesirable side effects. The glucagon receptor examined in the new study is just one member of a superfamily of GPCR surface cell receptors. GPCRs are the largest and most diverse group of membrane receptors in eukaryotes, (cells bearing a nucleus, including human cells). Signals that can be detected by GPCRs include light, peptides, lipids, sugars, and proteins. GPCRs perform a vast array of functions in the human body and their role in modern medicine is vast. Researchers estimate that between one-third and one-half of all marketed drugs act by binding to GPCRs and around 4 percent of the entire human genome is devoted to coding for these structures. While GPCRs bind a dizzying variety of signaling molecules, they share a common architecture that has been conserved over the course of evolution. Animals, plants, fungi, and protozoa all rely on GPCRs to receive information from their environment. Activation of GPCRs is involved with sensation, growth, hormone response and myriad other vital functions. The team used an antibody to stabilize the receptor ECD region, making it less dynamic and more suitable for crystallization, locking the receptor in a particular conformation in which the ECD, TMD and stalk region are held in a specific orientation. The resulting full-length structure exposed by X-ray crystallography differed significantly from earlier predictions of the receptor's shape based on modeling studies. (Antibodies like those used in the new study are being explored as possible ligands used to target the GCGP receptor and control diabetes.) "Now, we know how the ECD interacts with the ligand, so there can be much more directional development of drugs," Liu says. In addition to Liu's expertise in the realm of GPCRs, he and his ASU colleagues contributed sample preparation, data collection and analysis. A number of large pharmaceutical companies, (including Novo Nordisk, which supplied experimental binding compounds used in the current study), are now aggressively pursuing new therapies for diabetes based on the exquisitely detailed GPCR structures beginning to come to light.


- Structure of the full-length human glucagon receptor ignites new excitement in GPCR research SHANGHAI, May 18, 2017 /PRNewswire/ -- A team of scientists from Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences has determined the high-resolution atomic structure of a full-length class B G protein-coupled receptor (GPCR) that plays a key role in glucose homeostasis. This structure reveals, for the first time, the structural framework of different domains of a class B GPCR at high resolution and unexpectedly discloses many exciting molecular features, greatly deepening our understanding of signaling mechanisms of class B GPCRs. The new Nature study reports the crystal structure of the full-length human glucagon receptor (GCGR) that plays a key role in glucose homeostasis and serves as an important drug target for type 2 diabetes. The image shows the overall architecture of GCGR (grey cartoon, on the right), which consists of an extracellular domain and a transmembrane domain, in complex with an antibody mAb1 and a negative allosteric modulator NNC0640 (yellow sticks). The recently published cryo-electron microscopy structure of calcitonin receptor (cyan cartoon, on the left) bound to G protein, together with the full-length GCGR structure, highlighting the recent breakthroughs in class B GPCR research. (Image courtesy of Yekaterina Kadyshevskaya of the Bridge Institute at the University of Southern California.) In an article published online in Nature on May 17, 2017 (18:00PM, London time) titled "Structure of the full-length glucagon class B G protein-coupled receptor", scientists at SIMM, in collaboration with several groups based in China (ShanghaiTech University, Zhengzhou University and Fudan University), United States (University of Southern California, The Scripps Research Institute, Arizona State University and GPCR Consortium), the Netherlands (Vrije Universiteit Amsterdam) and Denmark (Novo Nordisk), provided a detailed molecular map of the full-length human glucagon receptor (GCGR) in complex with a negative allosteric modulator (NNC0640) and the antigen-binding fragment of an inhibitory antibody (mAb1). This study is published together in Nature with a companion paper led by colleagues at the iHuman Institute, ShanghaiTech University describing the glucagon-like peptide-1 receptor (GLP-1R). Class B GPCRs are essential to numerous physiological processes and serve as important drug targets for many human diseases such as type 2 diabetes, metabolic syndrome, osteoporosis, migraine, depression and anxiety. According to team leader and SIMM professor Dr. Beili Wu, "The GCGR structure provides a clear picture of a full-length class B GPCR at high resolution, and helps us understand how different domains cooperate in modulating the receptor function at the molecular level." Class B GPCR receptors consist of an extracellular domain (ECD) and a transmembrane domain (TMD), both of which are required to interact with their cognate peptide ligands and to regulate downstream signal transduction. Due to difficulties in high-quality protein preparation, structures of full-length class B GPCRs remained elusive, thus limiting a comprehensive understanding of molecular mechanisms of receptor action. This study gives some valuable insights into the structure of GCGR. The most exciting finding is that the linker region connecting the ECD and TMD of the receptor, termed the "stalk", works together with an extracellular loop of the TMD to regulate peptide binding through conformational changes, serving like a modulator in receptor activation. "Although the stalk region only contains 12 amino acids, it acts as a 'switch' to turn on or turn off the receptor," said Dr. Wu. "It is amazing to observe how a GPCR regulates its function in such a precise and efficient way." Based on the full-length GCGR structure, the researchers performed a series of functional studies using hydrogen-deuterium exchange, disulfide cross-linking, competitive ligand binding and cell signaling assays as well as molecular dynamics simulations. The results are in support of the GCGR structure and confirm the interactions between different domains in modulating its functionality via conformational alterations. "This study was carried out in a team effort with experts from different fields and different countries. International collaboration is of paramount importance in solving major problems in science nowadays," said Dr. Hualiang Jiang, Director of SIMM. "The full-length GCGR structure not only expands our knowledge about GPCR signaling mechanisms, but also offers new opportunities in drug discovery targeting class B GPCRs," said Dr. Ming-Wei Wang, Director of the National Center for Drug Screening. "With the information gained from this structure, we are in a better position to devise new therapeutic strategies involving both GCGR and glucagon-like peptide-1 receptor for obesity and type 2 diabetes." In addition to Drs. Wu, Wang and Jiang, other study investigators included Dr. Qiang Zhao, Dr. Dehua Yang and two graduate students (Haonan Zhang and Anna Qiao) from SIMM, Dr. Linlin Yang of Zhengzhou University and Dr. Raymond Stevens from the iHuman Institute, ShanghaiTech University. The study was funded by the National Basic Research Programs, the National Health and Family Planning Commission, the National Natural Science Foundation, Chinese Academy of Sciences, Shanghai Science and Technology Development Fund, GPCR Consortium and National Institutes of Health (U.S.A.). To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/a-first-full-length-class-b-gpcr-crystal-structure-reveals-novel-receptor-activation-mechanisms-300459023.html


News Article | May 17, 2017
Site: www.eurekalert.org

Type 2 diabetes, a prolific killer, is on a steep ascent. According to the World Health Organization, the incidence of the condition has grown dramatically from 108 million cases in 1980 to well over 400 million today. The complex disease occurs when the body's delicate regulation of glucose, a critical metabolite, is disrupted, creating a condition of elevated blood sugar known hyperglycemia. Over time, the condition can damage the heart, blood vessels, eyes, kidneys, and nerves. In a new study, Wei Liu and his colleagues at The Biodesign Institute join an international team, led by Beili Wu from the Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, to explore a central component in glucose regulation. Their findings shed new light on the structure of the glucagon receptor, a highly promising target for diabetes drug development. "The biggest highlight of this paper is that we now have a full-length structure of a class B GPCR," Liu says, referring to a specialized cell-surface receptor able to bind with signaling molecules and influence blood sugar regulation. In addition to ASU, scientists at SIMM, in collaboration with several groups based in China (ShanghaiTech University, Zhengzhou University and Fudan University), United States (University of Southern California, The Scripps Research Institute, and GPCR Consortium), the Netherlands (Vrije Universiteit Amsterdam) and Denmark (Novo Nordisk), provided a detailed molecular map of the full-length human glucagon receptor (GCGR) in complex with a modulator (NNC0640) and the antigen-binding antibody fragment (mAb1). The research appears in the advanced online edition of the journal Nature. GPCRs (for G-Protein Coupled Receptors) are specialized receptors adorning cell surfaces. They act like email inboxes for important messages, which arrive at the outer membrane in the form of binding molecules or ligands that affect cell behavior and regulation. Receptor-ligand binding alters the conformation of the receptor and sends messages to the cell's interior, guiding cell function. Pharmaceutical companies hope to develop new drugs that can more accurately and efficiently bind with cell receptors, including diabetes drugs that will be able to halt or reduce the overproduction of glucose. The detailed structure of the glucagon receptor (or "GCGR") examined in the study was solved using the technique of X-ray crystallography. Here, a crystallized protein is struck with X-rays, which form a diffraction pattern that can be reassembled into an extremely detailed picture of the sample. Such information is vital for the development of effective drugs, which must bind with their complex target cell receptors with great specificity. Binding of a specific ligand to the glucagon receptor triggers the release of glucose from the liver during fasting, making this receptor a critical component for maintaining normal glucose levels in the body. Class B GPCRs are essential to numerous physiological processes and serve as important drug targets for many human diseases such as type 2 diabetes, metabolic syndrome, osteoporosis, migraine, depression and anxiety. According to team leader and SIMM professor Dr. Beili Wu, "The GCGR structure provides a clear picture of a full-length class B GPCR at high resolution, and helps us understand how different domains cooperate in modulating the receptor function at the molecular level." The GCGR receptor consists of three key components: an extracellular domain (ECD), which protrudes above the surface of the cell, a transmembrane domain (TCD), which is anchored into the cell membrane itself and a region known as the stalk, which connects the two domains and acts as a kind of pivot. (Figure 1 shows the basic structure of the GCGR receptor made up of an extracellular domain, stalk region and transmembrane region. Also pictured is the binding antibody mAb23.) The results of the new study are significant because all three parts of the receptor are essential for its ability to properly bind with its target molecules."Previously we had solved the structure for this GPCR, but we had truncated the whole extracellular domain, which is a critical part for ligand binding," Liu says. Further, although the stalk region contains just 12 amino acids, it is critical for activating and de-activating the GCGR receptor. Progressive diabetes can result in serious health complications, including heart disease, blindness, kidney failure, and lower-extremity amputations. It is currently the seventh leading cause of death in the United States. Proper regulation of blood sugar levels relies on two key hormones, which together act like a kind of thermostat. When blood sugar becomes elevated above the normal threshold, insulin is produced by islet cells in the pancreas, acting to keep blood sugar in check. But an even greater risk to the body occurs should blood sugar fall dangerously low. Indeed, low blood sugar or hypoglycemia can be fatal as glucose is the most important brain metabolite, essential for survival. Under conditions of hypoglycemia, another hormone, known as glucagon is produced by pancreatic α-cells. Glucagon acts as the main counter-regulatory hormone, opposing the action of insulin and switching on glucose production in the liver during fasting. Glucagon influences target tissues through activation of the GCGR receptor. In Type 2 diabetes, insulin production is impaired, leading to elevated blood sugar. Treatment for the disease with supplemental insulin has therefore been a therapy of choice for most patients of the disease. But diabetes also affects glucagon production through dysregulation of the GCGR receptor, causing the overproduction of glucose. The combination of insulin deficiency and glucose excess is typical of Type II diabetes and calls for a multi-pronged approach to addressing the disease. The idea of targeting the GCGR receptor with drugs able to bind with it and switch it off has long been proposed and experiments in rats indicate that the approach is sound. Much more work is required however to perform the same feat in humans. Now, with the complete structure of the receptor in hand, pharmaceutical companies are poised to develop much more effective drugs that specifically target glucose production, while avoiding undesirable side effects. The glucagon receptor examined in the new study is just one member of a superfamily of GPCR surface cell receptors. GPCRs are the largest and most diverse group of membrane receptors in eukaryotes, (cells bearing a nucleus, including human cells). Signals that can be detected by GPCRs include light, peptides, lipids, sugars, and proteins. GPCRs perform a vast array of functions in the human body and their role in modern medicine is vast. Researchers estimate that between one-third and one-half of all marketed drugs act by binding to GPCRs and around 4 percent of the entire human genome is devoted to coding for these structures. While GPCRs bind a dizzying variety of signaling molecules, they share a common architecture that has been conserved over the course of evolution. Animals, plants, fungi, and protozoa all rely on GPCRs to receive information from their environment. Activation of GPCRs is involved with sensation, growth, hormone response and myriad other vital functions. The team used an antibody to stabilize the receptor ECD region, making it less dynamic and more suitable for crystallization, locking the receptor in a particular conformation in which the ECD, TMD and stalk region are held in a specific orientation. The resulting full-length structure exposed by X-ray crystallography differed significantly from earlier predictions of the receptor's shape based on modeling studies. (Antibodies like those used in the new study are being explored as possible ligands used to target the GCGP receptor and control diabetes.) "Now, we know how the ECD interacts with the ligand, so there can be much more directional development of drugs," Liu says. In addition to Liu's expertise in the realm of GPCRs, he and his ASU colleagues contributed sample preparation, data collection and analysis. A number of large pharmaceutical companies, (including Novo Nordisk, which supplied experimental binding compounds used in the current study), are now aggressively pursuing new therapies for diabetes based on the exquisitely detailed GPCR structures beginning to come to light.


News Article | May 17, 2017
Site: www.rdmag.com

Type 2 diabetes, a prolific killer, is on a steep ascent. According to the World Health Organization, the incidence of the condition has grown dramatically from 108 million cases in 1980 to well over 400 million today. The complex disease occurs when the body's delicate regulation of glucose, a critical metabolite, is disrupted, creating a condition of elevated blood sugar known hyperglycemia. Over time, the condition can damage the heart, blood vessels, eyes, kidneys, and nerves. In a new study, Wei Liu and his colleagues at The Biodesign Institute join an international team, led by Beili Wu from the Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, to explore a central component in glucose regulation. Their findings shed new light on the structure of the glucagon receptor, a highly promising target for diabetes drug development. "The biggest highlight of this paper is that we now have a full-length structure of a class B GPCR," Liu says, referring to a specialized cell-surface receptor able to bind with signaling molecules and influence blood sugar regulation. In addition to ASU, scientists at SIMM, in collaboration with several groups based in China (ShanghaiTech University, Zhengzhou University and Fudan University), United States (University of Southern California, The Scripps Research Institute, and GPCR Consortium), the Netherlands (Vrije Universiteit Amsterdam) and Denmark (Novo Nordisk), provided a detailed molecular map of the full-length human glucagon receptor (GCGR) in complex with a modulator (NNC0640) and the antigen-binding antibody fragment (mAb1). The research appears in the advanced online edition of the journal Nature. GPCRs (for G-Protein Coupled Receptors) are specialized receptors adorning cell surfaces. They act like email inboxes for important messages, which arrive at the outer membrane in the form of binding molecules or ligands that affect cell behavior and regulation. Receptor-ligand binding alters the conformation of the receptor and sends messages to the cell's interior, guiding cell function. Pharmaceutical companies hope to develop new drugs that can more accurately and efficiently bind with cell receptors, including diabetes drugs that will be able to halt or reduce the overproduction of glucose. The detailed structure of the glucagon receptor (or "GCGR") examined in the study was solved using the technique of X-ray crystallography. Here, a crystallized protein is struck with X-rays, which form a diffraction pattern that can be reassembled into an extremely detailed picture of the sample. Such information is vital for the development of effective drugs, which must bind with their complex target cell receptors with great specificity. Binding of a specific ligand to the glucagon receptor triggers the release of glucose from the liver during fasting, making this receptor a critical component for maintaining normal glucose levels in the body. Class B GPCRs are essential to numerous physiological processes and serve as important drug targets for many human diseases such as type 2 diabetes, metabolic syndrome, osteoporosis, migraine, depression and anxiety. According to team leader and SIMM professor Dr. Beili Wu, "The GCGR structure provides a clear picture of a full-length class B GPCR at high resolution, and helps us understand how different domains cooperate in modulating the receptor function at the molecular level." The GCGR receptor consists of three key components: an extracellular domain (ECD), which protrudes above the surface of the cell, a transmembrane domain (TCD), which is anchored into the cell membrane itself and a region known as the stalk, which connects the two domains and acts as a kind of pivot. (Figure 1 shows the basic structure of the GCGR receptor made up of an extracellular domain, stalk region and transmembrane region. Also pictured is the binding antibody mAb23.) The results of the new study are significant because all three parts of the receptor are essential for its ability to properly bind with its target molecules."Previously we had solved the structure for this GPCR, but we had truncated the whole extracellular domain, which is a critical part for ligand binding," Liu says. Further, although the stalk region contains just 12 amino acids, it is critical for activating and de-activating the GCGR receptor. Progressive diabetes can result in serious health complications, including heart disease, blindness, kidney failure, and lower-extremity amputations. It is currently the seventh leading cause of death in the United States. Proper regulation of blood sugar levels relies on two key hormones, which together act like a kind of thermostat. When blood sugar becomes elevated above the normal threshold, insulin is produced by islet cells in the pancreas, acting to keep blood sugar in check. But an even greater risk to the body occurs should blood sugar fall dangerously low. Indeed, low blood sugar or hypoglycemia can be fatal as glucose is the most important brain metabolite, essential for survival. Under conditions of hypoglycemia, another hormone, known as glucagon is produced by pancreatic α-cells. Glucagon acts as the main counter-regulatory hormone, opposing the action of insulin and switching on glucose production in the liver during fasting. Glucagon influences target tissues through activation of the GCGR receptor. In Type 2 diabetes, insulin production is impaired, leading to elevated blood sugar. Treatment for the disease with supplemental insulin has therefore been a therapy of choice for most patients of the disease. But diabetes also affects glucagon production through dysregulation of the GCGR receptor, causing the overproduction of glucose. The combination of insulin deficiency and glucose excess is typical of Type II diabetes and calls for a multi-pronged approach to addressing the disease. The idea of targeting the GCGR receptor with drugs able to bind with it and switch it off has long been proposed and experiments in rats indicate that the approach is sound. Much more work is required however to perform the same feat in humans. Now, with the complete structure of the receptor in hand, pharmaceutical companies are poised to develop much more effective drugs that specifically target glucose production, while avoiding undesirable side effects. The glucagon receptor examined in the new study is just one member of a superfamily of GPCR surface cell receptors. GPCRs are the largest and most diverse group of membrane receptors in eukaryotes, (cells bearing a nucleus, including human cells). Signals that can be detected by GPCRs include light, peptides, lipids, sugars, and proteins. GPCRs perform a vast array of functions in the human body and their role in modern medicine is vast. Researchers estimate that between one-third and one-half of all marketed drugs act by binding to GPCRs and around 4 percent of the entire human genome is devoted to coding for these structures. While GPCRs bind a dizzying variety of signaling molecules, they share a common architecture that has been conserved over the course of evolution. Animals, plants, fungi, and protozoa all rely on GPCRs to receive information from their environment. Activation of GPCRs is involved with sensation, growth, hormone response and myriad other vital functions. The team used an antibody to stabilize the receptor ECD region, making it less dynamic and more suitable for crystallization, locking the receptor in a particular conformation in which the ECD, TMD and stalk region are held in a specific orientation. The resulting full-length structure exposed by X-ray crystallography differed significantly from earlier predictions of the receptor's shape based on modeling studies. (Antibodies like those used in the new study are being explored as possible ligands used to target the GCGP receptor and control diabetes.) "Now, we know how the ECD interacts with the ligand, so there can be much more directional development of drugs," Liu says. In addition to Liu's expertise in the realm of GPCRs, he and his ASU colleagues contributed sample preparation, data collection and analysis. A number of large pharmaceutical companies, (including Novo Nordisk, which supplied experimental binding compounds used in the current study), are now aggressively pursuing new therapies for diabetes based on the exquisitely detailed GPCR structures beginning to come to light.


In an article published online in Nature on May 17, 2017 (18:00PM, London time) titled "Structure of the full-length glucagon class B G protein-coupled receptor", scientists at SIMM, in collaboration with several groups based in China (ShanghaiTech University, Zhengzhou University and Fudan University), United States (University of Southern California, The Scripps Research Institute, Arizona State University and GPCR Consortium), the Netherlands (Vrije Universiteit Amsterdam) and Denmark (Novo Nordisk), provided a detailed molecular map of the full-length human glucagon receptor (GCGR) in complex with a negative allosteric modulator (NNC0640) and the antigen-binding fragment of an inhibitory antibody (mAb1). This study is published together in Nature with a companion paper led by colleagues at the iHuman Institute, ShanghaiTech University describing the glucagon-like peptide-1 receptor (GLP-1R). Class B GPCRs are essential to numerous physiological processes and serve as important drug targets for many human diseases such as type 2 diabetes, metabolic syndrome, osteoporosis, migraine, depression and anxiety. According to team leader and SIMM professor Dr. Beili Wu, "The GCGR structure provides a clear picture of a full-length class B GPCR at high resolution, and helps us understand how different domains cooperate in modulating the receptor function at the molecular level." Class B GPCR receptors consist of an extracellular domain (ECD) and a transmembrane domain (TMD), both of which are required to interact with their cognate peptide ligands and to regulate downstream signal transduction. Due to difficulties in high-quality protein preparation, structures of full-length class B GPCRs remained elusive, thus limiting a comprehensive understanding of molecular mechanisms of receptor action. This study gives some valuable insights into the structure of GCGR. The most exciting finding is that the linker region connecting the ECD and TMD of the receptor, termed the "stalk", works together with an extracellular loop of the TMD to regulate peptide binding through conformational changes, serving like a modulator in receptor activation. "Although the stalk region only contains 12 amino acids, it acts as a 'switch' to turn on or turn off the receptor," said Dr. Wu. "It is amazing to observe how a GPCR regulates its function in such a precise and efficient way." Based on the full-length GCGR structure, the researchers performed a series of functional studies using hydrogen-deuterium exchange, disulfide cross-linking, competitive ligand binding and cell signaling assays as well as molecular dynamics simulations. The results are in support of the GCGR structure and confirm the interactions between different domains in modulating its functionality via conformational alterations. "This study was carried out in a team effort with experts from different fields and different countries. International collaboration is of paramount importance in solving major problems in science nowadays," said Dr. Hualiang Jiang, Director of SIMM. "The full-length GCGR structure not only expands our knowledge about GPCR signaling mechanisms, but also offers new opportunities in drug discovery targeting class B GPCRs," said Dr. Ming-Wei Wang, Director of the National Center for Drug Screening. "With the information gained from this structure, we are in a better position to devise new therapeutic strategies involving both GCGR and glucagon-like peptide-1 receptor for obesity and type 2 diabetes." In addition to Drs. Wu, Wang and Jiang, other study investigators included Dr. Qiang Zhao, Dr. Dehua Yang and two graduate students (Haonan Zhang and Anna Qiao) from SIMM, Dr. Linlin Yang of Zhengzhou University and Dr. Raymond Stevens from the iHuman Institute, ShanghaiTech University. The study was funded by the National Basic Research Programs, the National Health and Family Planning Commission, the National Natural Science Foundation, Chinese Academy of Sciences, Shanghai Science and Technology Development Fund, GPCR Consortium and National Institutes of Health (U.S.A.). To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/a-first-full-length-class-b-gpcr-crystal-structure-reveals-novel-receptor-activation-mechanisms-300459023.html


News Article | May 5, 2017
Site: en.prnasia.com

WUXI, China, May 6, 2017 /PRNewswire/ -- The final round of the 2017 ASC Student Supercomputer Challenge (ASC17) ended in Wuxi. Tsinghua University stood out from 20 teams from around the world after a fierce one-week competition, becoming grand champion and winning the prize. As the world's largest supercomputing competition, ASC17 received applications from 230 universities around the world, 20 of which got through to the final round held this week at the National Supercomputing Center in Wuxi after the qualifying rounds. During the final round, the university student teams were required to independently design a supercomputing system under the precondition of a limited 3000W power consumption. They also had to operate and optimize standard international benchmark tests and a variety of cutting-edge scientific and engineering applications including AI-based transport prediction, genetic assembly, and material science. Moreover, they were required to complete high-resolution maritime simulation on the world's fastest supercomputer, "Sunway TaihuLight". The grand champion, team Tsinghua University, completed deep parallel optimization of the high-resolution maritime data simulation mode MASNUM on TaihuLight, expanding the original program up to 10,000 cores and speeding up the program by 392 times. This helped the Tsinghua University team win the e Prize award. MASNUM was nominated in 2016 for the Gordon Bell Prize, the top international prize in the supercomputing applications field. The runner-up, Beihang University, gave an outstanding performance in the popular AI field. After constructing a supercomputing system which received massive training based on past big data of transportation provided by Baidu, their self-developed excellent deep neural network model yielded the most accurate prediction of road conditions during the morning peak. The first-time finalist, Weifang University team, constructed a highly optimized advanced heterogeneous supercomputing system with Inspur's supercomputing server, and ran the international HPL benchmark test, setting a new world record of 31.7 TFLOPS for float-point computing speed. The team turned out to be the biggest surprise of the event and won the award for best computing performance. Moreover, Ural Federal University, National Tsing Hua University, Northwestern Polytechnical University and Shanghai Jiao Tong University won the application innovation award. The popular choice award was shared by Saint-Petersburg State University and Zhengzhou University. "It is great to see the presence of global teams in this event," Jack Dongarra, the Chairman of the ASC Expert Committee, founder of the TOP500 list that ranks the 500 most powerful supercomputer systems in the world, and professor at the Oak Ridge National Laboratory of the United States and the University of Tennessee, said in an interview. "This event inspired students to gain advanced scientific knowledge. TaihuLight is an amazing platform for this event. Just imagine the interconnected computation of everyone's computer in a gymnasium housing 100,000 persons, and TaihuLight's capacity is 100 times of such a gym. This is something none of the teams will ever be able to experience again." According to Wang Endong, initiator of the ASC competition, academician of the Chinese Academy of Engineering, and the chief scientist of Inspur Group, the rapid development of AI at the moment is significantly changing human society. At the core of such development are computing, data and algorithms. With this trend, supercomputers will become an important infrastructure for intelligent society in the future, and their speed of development and standards will be closely related to social development, improvement in livelihood, and progress of civilization. ASC competition is always committed to cultivating future-oriented, inter-disciplinary supercomputing talents to extend the benefits to the greater population. ASC17 is jointly organized by the Asian Supercomputing Community, Inspur Group, the National Supercomputing Center in Wuxi, and Zhengzhou University. Initiated by China, the ASC supercomputing challenge aims to be the platform to promote exchanges among young supercomputing talent from different countries and regions, as well as to groom young talent. It also aims to be the key driving force in promoting technological and industrial innovations by improving the standards in supercomputing applications and research. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/tsinghua-university-won-asc17-championship-big-time-300452166.html

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