News Article | December 22, 2016
LA JOLLA, CA - December 21, 2016 - A new study led by scientists at The Scripps Research Institute (TSRI) is the first to show exactly how the drug Arbidol stops influenza infections. The research reveals that Arbidol stops the virus from entering host cells by binding within a recessed pocket on the virus. The researchers believe this new structural insight could guide the development of future broad-spectrum therapeutics that would be even more potent against influenza virus. "This is a very interesting molecule, and now we know where it binds and precisely how it works," said study senior author Ian Wilson, Hanson Professor of Structural Biology, chair of the Department of Integrative Structural and Computational Biology and member of the Skaggs Institute for Chemical Biology at TSRI. The study was published today in the journal Proceedings of the National Academy of Sciences. Arbidol (also called umifenovir) is an anti-flu treatment sold in Russia and China by the Russian pharmaceutical company Pharmstandard. The drug is currently in stage-four clinical trials in the United States. The drug targets many strains of influenza, giving it an advantage over seasonal vaccines that target only a handful of strains. The new study sheds light on exactly how it accomplishes this feat. Scientists had long been curious whether Arbidol bound to the viral proteins used to recognize host cells--or with the viral "fusion machinery" that enters and infects host cells. To answer this question, the researchers used a high-resolution imaging technique called X-ray crystallography to create 3D structures showing how Arbidol binds to two different strains of influenza virus. The structures revealed that Arbidol binds to the virus's fusion machinery, as some had suspected. The small molecule binds to a viral protein called hemagglutinin, stopping the virus from rearranging its conformation in a way that enables the virus to fuse its membrane with a host cell. "We found that the small molecule binds to a hidden pocket in hemagglutinin," said study first author Rameshwar U. Kadam, senior research associate at TSRI. He added that the drug acts as a sort of "glue" to hold the subunits of hemagglutinin together. "Arbidol is the first influenza treatment shown to use a hemagglutinin-binding approach," he said. This vulnerable pocket is "conserved," meaning it is likely important for viral function--and more difficult to mutate as the virus spreads--suggesting why Arbidol has relatively broad use in fighting many strains of the virus, including emerging strains. The new findings also help scientists understand how Arbidol compares to influenza treatments such as Tamiflu. Wilson explained that Tamiflu prevents the virus from getting out of cells, while Arbidol prevents it from getting in. This means Arbidol, or future drugs that take a similar approach, could be given as a preventative treatment before an outbreak hits. "When we had the 2009 H1N1 pandemic, the vaccine came too late," said Wilson. "If we had a front-line therapeutic, that could have worked much better until a vaccine was ready." Wilson said the next step for researchers is to discover and/or design other small molecule therapeutics that can bind even more tightly with the hemagglutinin. This study, "Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol," was supported by the National Institutes of Health (grant R56 AI117675) and an Early Mobility Postdoctoral Fellowship from the Swiss National Science Foundation. This study used resources funded in whole or in part by the National Cancer Institute (grant Y1-CO-1020); the National Institute of General Medical Science (grant Y1-GM-1104); the U.S. Department of Energy, Basic Energy Sciences, Office of Science (contracts DE-AC02-06CH11357 and DE-AC02-76SF00515); the U.S. Department of Energy, Office of Biological and Environmental Research and by the National Institute of General Medical Science (grant P41GM103393). The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .
News Article | December 5, 2016
Some sea creatures cover themselves with hard shells and spines, while vertebrates build skeletons out of the same minerals. How do these animals get the calcium they need to build these strong mineral structures? Professors Lia Addadi and Steve Weiner of the Weizmann Institute of Science's Structural Biology Department asked this question about sea urchins, which need to extract quite a few calcium ions from sea water to build their spines. The answer surprised them, and it could change the way scientists think about the process of biomineralization. Several years ago, Addadi and Weiner had discovered that sea urchins build their spines with tiny packets of "unorganized" material that hardens into crystal when laid in place. "So the question went back a step: How do they get the calcium ions they need to make this material in the first place?" says Addadi. "Free calcium is not abundant in sea water," adds Weiner, "so they need an efficient way to extract and concentrate the ions." To answer the question the researchers, including Netta Vidavsky, needed methods to observe the animal's cells "as is," that is, as they are in life, water included. For this the group turned to Dr. Andreas Schertel of Carl Zeiss Microscopy in Germany and Dr. Sefi Addadi of the Weizmann Institute of Science's Life Sciences Core Facilities. Very new cutting-edge techniques enabled them to observe thin slices of the cells in sea urchin embryos and then to reconstruct three-dimensional images of these cells and their intake of labeled calcium ions. "Even a few years ago, we could not have done this study," says Addadi. The images showed that sea urchin larval cells actually "drink" seawater, taking in drops of water and manipulating the ions in the water within the confines of the cell. This is in contrast to the theory that these cells take in only ions, one at a time, through special channels in their outer membranes. The cells they observed were filled with networks of bubbles called vacuoles that collect the calcium ions, evidently creating concentrated packages of calcium for building the spines. This method may be more energy efficient than taking in ions through channels (which the cells also did), but it presents another problem: The cells must be able to pick out the calcium as well as expel other ions in the sea water, especially the sodium and chloride. "Researchers may be busy for years to come figuring out how these cells manipulate the ions in the sea water they drink," says Weiner. Addadi and Weiner point out that this is not the first time this type of calcium ion intake has been observed. Prof. Jonathan Erez of the Hebrew University of Jerusalem had described this phenomenon in single-celled, hard-shelled microorganisms called foraminifera a decade ago. At the time, it was thought to be a "curiosity," but finding the same process in two very different creatures suggests that it may be quite widespread. Although we do not live in sea water, even the cells that build our bones may use a similar method to obtain calcium. Prof. Lia Addadi's research is supported by the Jeanne and Joseph Nissim Foundation for Life Sciences Research. Prof. Lia Addadi is the incumbent of the Dorothy and Patrick Gorman Professorial Chair. Prof. Stephen Weiner's research is supported by the Helen and Martin Kimmel Center for Archaeological Science, which he heads; the Dangoor Accelerator Mass Spectrometer Laboratory; and the estate of George and Beatrice F. Schwartzman. Prof. Weiner is the incumbent of the Dr. Walter and Dr. Trude Borchardt Professorial Chair in Structural Biology. The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
News Article | February 22, 2017
A Phase 1 clinical trial to test the safety and tolerability of an investigational vaccine against respiratory syncytial virus (RSV) has begun at the National Institutes of Health Clinical Center in Bethesda, Maryland. The trial also will assess the vaccine's ability to prompt an immune response in healthy adult participants. The investigational vaccine was developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. Most people are infected with RSV by age 2 and undergo repeated infections throughout life. Infected adults and children generally experience mild, cold-like symptoms that resolve within a week or two. However, infection can cause severe lower respiratory tract disease, including pneumonia and bronchiolitis, among premature infants, children younger than age 2 with heart or lung problems, children and adults with weakened immune systems and the elderly. About 2 percent of RSV-infected infants under 1 year of age require hospitalization. Children between ages 1 and 5 years and adults older than 65 years are also at higher risk of hospitalization. Each year on average in the United States, RSV leads to 57,527 hospitalizations and 2.1 million outpatient visits among children younger than 5 years; and 177,000 hospitalizations and 14,000 deaths among adults older than 65 years, according to the Centers for Disease Control and Prevention. Globally, RSV infections are estimated to cause more than 250,000 deaths each year. Currently no vaccine to prevent RSV infection or drug to treat it is available. The monoclonal antibody palivizumab is licensed in the U.S. for preventing serious lower respiratory tract disease caused by RSV in high-risk children, but it is not licensed for use in the general population. "RSV is underappreciated as a major cause of illness and death, not only in infants and children but also in people with weakened immune systems and the elderly," said NIAID Director Anthony S. Fauci, M.D. "A vaccine to reduce the burden of this important disease is badly needed." The study, called VRC 317, will enroll healthy adults ages 18-50 years. Participants will be randomly assigned to receive two injections in the arm at 12 weeks apart with either the investigational vaccine or the investigational vaccine adjuvanted with alum. Alum is a chemical compound commonly added to vaccines to enhance the body's immune response. Participants will also be randomly assigned to receive one of three vaccine doses (50 micrograms, 150 micrograms or 500 micrograms) at both vaccination time points. Initially, five people will be vaccinated with the 50 microgram dose. If the initial group of participants experience no serious adverse reactions attributable to the vaccine, the study team will then begin to vaccinate participants at the next dosage level. They will repeat this stepwise process until they administer the 500 microgram dose. Participants will return for 12 clinic visits over 44 weeks after the first injection. At these visits, study clinicians will conduct physical exams and collect blood samples. They will also test mucous samples from volunteers' mouths and noses to measure the immune responses generated. The study is being led by principal investigator Michelle C. Crank, M.D., head of the Translational Sciences Core in the Viral Pathogenesis Laboratory part of NIAID's Vaccine Research Center (VRC). Study clinicians will conduct a daily safety review of any new clinical information, and a Protocol Safety Review Team will examine trial safety data weekly to ensure the vaccine meets safety standards. The investigational vaccine, called DS-Cav1, results from years of research led by Barney S. Graham, M.D., Ph.D., deputy VRC director, and Peter D. Kwong, Ph.D., chief of the Structural Biology Section and the Structural Bioinformatics Core at the VRC. The vaccine candidate is a single, structurally-engineered protein from the surface of RSV rather than a more traditional approach based on a weakened or inactivated whole virus. In 2013, VRC scientists tested several versions of the protein as a vaccine in mice and nonhuman primates. The protein variants elicited high levels of neutralizing antibodies and protected the animals against RSV infection. Drs. Graham and Kwong selected the most promising candidate, DS-Cav1, for clinical evaluation. "This work represents an example of how new biological insights from basic research can lead to candidate vaccines for diseases of public health importance, and the value of multidisciplinary research teams like the ones assembled at the VRC," said Dr. Graham. The trial is expected to take one year to complete. For more information about the trial, visit clinicaltrials.gov and search identifier NCT03049488. For more information, visit about NIAID's Respiratory Syncytial Virus (RSV) web page. NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website. About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www. .
News Article | March 2, 2017
DUBLIN--(BUSINESS WIRE)--Research and Markets has announced the addition of the "Structural Biology & Molecular Modeling Techniques Market Analysis By Tools, By Application And Segment Forecasts 2014 - 2025" report to their offering. The structural biology & molecular modeling techniques market is expected to reach USD 13.1 billion by 2025 An unprecedented rise in the adoption of unhealthy lifestyles has led to an upsurge in the prevalence of chronic diseases, such as diabetes and cancer, which is presumed to propel the structural biology & molecular modeling techniques market during the forecast period. Moreover, increasing drug resistance coupled with the high drug attrition rate is engendering the requirement for extensive R&D activities, which is presumed to boost the adoption of structural biology & molecular modeling techniques in the drug discovery and development process. This is expected to serve as an efficient approach in fast tracking the development of drugs with high potency. The heightening demand for molecular modeling techniques is predominantly attributable to the significant cost reduction enabled. This is due to the fact that prediction software identifies possible adverse reactions and determines drug efficacy and toxicity in the pre-clinical stages, thereby reducing the probability of drug failure at the later stages. Consequentially, the aforementioned factors serve as prominent reasons responsible for the widened market demand. For more information about this report visit http://www.researchandmarkets.com/research/fxhk2b/structural
News Article | November 29, 2016
The Fas protein can either inhibit or promote the controlled cell death (apoptosis), depending on the isoform in which it occurs. Together with international colleagues, researchers from the Helmholtz Zentrum München and the Technical University of Munich have elucidated how this decision is guided. These results provide new insights into the molecular mechanisms of tumor diseases and have now been published in eLife. Please find a video of the PI explaining the story here: https:/ We know the problem: When assembling the parts and pieces of furniture purchased at a store, everyone uses the same blueprint. Nevertheless, the end product can differ greatly in the course of assembling the whole product over several intermediate steps. Something quite similar can happen during the production of proteins from genes. The genome (the blueprint) is first transcribed into a messenger molecule, the mRNA, and then translated into proteins (furniture). However, the mRNA can be altered and trimmed during intermediate steps in a process called alternative splicing, so that ultimately different proteins are produced from the same blueprint. An interesting example of alternative splicing is the mRNA of the Fas gene*. Depending on which intermediate steps take place, the finished protein can either prevent or promote controlled cell death (apoptosis). "The right balance between these opposing results is dependent on the cell type and can also lead to uncontrolled cell growth and cancer when alternative splicing is dysregulated," explains Professor Michael Sattler, Director of the Institute of Structural Biology (STB) at Helmholtz Zentrum München. In collaboration with Professor Juan Valcárcel Juárez of the Centre de Regulació Genòmica (CRG) in Barcelona, he and his team have now gained insight into which intermediate steps are taken and how these lead to different isoforms of the Fas protein. "The focus of our interest was the protein RBM5, which often exhibits mutations in lung tumors," says Dr. André Mourão of the STB. "RBM5 helps to bring the spliceosome to the mRNA by binding to a spliceosomal protein", explains coauthor Dr. Sophie Bonnal of the CRG Barcelona. In this central position, RBM5 decides which isoform of Fas is expressed and thus controls the balance between the two different isoforms.** "By employing nuclear magnetic resonance (NMR) spectroscopy at the Bavarian NMR Center in Garching, we were able to elucidate the spatial structure of RBM5-OCRE in complex with SmN (a protein present in the spliceosome) and to understand exactly how these interaction occurs," states Sattler, who directed the study.*** To confirm their findings, the scientists mutated the corresponding interaction residues of the proteins and observed that the interactions no longer took place in the test tube and that the splicing activities of RBM5 in cell culture was impaired. "The process of alternative splicing affects numerous essential functions and processes in an organism, and dysregulation can trigger cancer. That is why it is very important to precisely understand the mechanisms that regulate these processes," explains Sattler, summarizing the results. According to the authors, only a few protein interactions that influence alternative splicing by binding to spliceosomal proteins have been analyzed in such structural depth. In the future, the researchers want to determine exactly how RBM5 binds to the mRNA and whether there are additional interactions with the spliceosome, which consists of numerous other components. * Fas is also known as CD95 or APO-1. Depending on whether a specific region (exon 6) is contained in the mRNA or not, a membrane-bound pro-apoptotic protein or a soluble isoform arises in the cell interior, which counteracts apoptosis. As a pro-apoptotic protein, Fas prevents errant cells from multiplying uncontrolled, whereas the anti-apoptotic isoform leads to the proliferation of such cells. ** The name is an acronym for RNA Binding Motif 5. RBM5 is a protein, which is demonstrably dysregulated in different cancers (especially in the lungs). *** A so-called OCRE (octamer repeat of aromatic residues) domain of the protein RBM5 binds to the C-terminus of the spliceosomal protein SmN and is thus important for the regulation of the alternative splicing. Background: In addition to his work at Helmholtz Zentrum München, Prof. Dr. Sattler holds the chair of Biomolecular NMR Spectroscopy at Technische Universität München. He heads the Bavarian NMR Center, which is jointly operated by TUM and HMGU (http://www. ). The Institució Catalana de Recerca i Estudis Avançats (ICREA) in Barcelona in Spain (http://www. ) and the Institut de Génétique Moléculaire de Montpellier in France also participated in the study. Publication: Mourão, A. & Bonnal, S. & Soni, K. & Warner, L. et al. (2016): Structural basis for the recognition of spliceosomal SmN/B/B' proteins by the RBM5 OCRE domain in splicing regulation. eLife, doi: 10.7554/eLife.14707 https:/ The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www. The Institute for Structural Biology (STB) investigates the spatial structures of biological macromolecules, their molecular interactions and dynamics using integrated structural biology by combining X-ray crystallography, NMR-spectroscopy and other methods. Researchers at STB also develop NMR spectroscopy methods for these studies. The goal is to unravel the structural and molecular mechanisms underlying biological function and their impairment in disease. The structural information is used for the rational design and development of small molecular inhibitors in combination with chemical biology approaches. http://www. Technical University of Munich (TUM) is one of Europe's leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 40,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, combined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany. http://www. Contact for the media: Department of Communication, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 2238 - Fax: +49 89 3187 3324 - E-mail: email@example.com Scientific Contact at Helmholtz Zentrum München: Prof. Dr. Michael Sattler, Helmholtz Zentrum München - German Research Center for Environmental Health, Institute for Structural Biology, Ingolstädter Landstraße 1, 85764 Neuherberg, Tel. +49 89 3187 3800, E-mail: firstname.lastname@example.org
News Article | February 15, 2017
SAN DIEGO--(BUSINESS WIRE)--Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) announces the appointment of Christel Iffland, Ph.D. as a Vice President of Antibody Technologies. Dr. Iffland joins Ligand from Merck KGaA/EMD Serono where she served as Group Leader of Antibody Display Technologies, a Senior Scientist of Phage Technologies and Structural Biology and Associate Director of Antibody Technologies. At Ligand, Dr. Iffland will support current and new partnerships and collaborations for the OmniAb franchise, providing scientific guidance and input. Additionally, she will contribute to the continued growth and next-generation innovation of OmniAb and to the technical assessment of new opportunities. “Christel has been a longtime user of the OmniAb technology and we are delighted to welcome her to Ligand as we further expand our scientific team focused on antibodies and antibody technologies,” said John Higgins, Ligand’s Chief Executive Officer. “Our acquisition of the OmniAb technology last year transformed and expanded Ligand’s business model. Antibody treatments are the fastest-growing segment of the pharmaceutical industry and will continue to be an important area of focus for Ligand as we expand our portfolio of more than 150 fully-funded shots-on-goal.” Dr. Iffland received her Ph.D. in Molecular and Cell Biology from the Université de Nice Sophia-Antipolis in Nice, France and completed post-doctoral research training at both the Dana-Farber Cancer Institute at Harvard Medical School and the Albert Einstein College of Medicine. Dr. Iffland is an author of numerous scientific publications and patents and is a prior recipient of the Merck Award for Patent and Inventorship. OmniAb includes three transgenic animal platforms for producing mono- and bispecific human therapeutic antibodies. OmniRat® is the industry’s first human monoclonal antibody technology based on rats. It has a complete immune system with a diverse antibody repertoire and generates antibodies with human idiotypes as effectively as wild-type animals make rat antibodies. OmniMouse® is a transgenic mouse that complements OmniRat and expands epitope coverage. OmniFlic® is an engineered rat with a fixed light chain for development of bispecific, fully human antibodies. The three platforms use patented technology, have broad freedom to operate and deliver fully human antibodies with high affinity, specificity, expression, solubility and stability. Ligand is a biopharmaceutical company focused on developing or acquiring technologies that help pharmaceutical companies discover and develop medicines. Our business model creates value for stockholders by providing a diversified portfolio of biotech and pharmaceutical product revenue streams that are supported by an efficient and low corporate cost structure. Our goal is to offer investors an opportunity to participate in the promise of the biotech industry in a profitable, diversified and lower-risk business than a typical biotech company. Our business model is based on doing what we do best: drug discovery, early-stage drug development, product reformulation and partnering. We partner with other pharmaceutical companies to leverage what they do best (late-stage development, regulatory management and commercialization) to ultimately generate our revenue. Ligand’s Captisol® platform technology is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. OmniAb® is a patent-protected transgenic animal platform used in the discovery of fully human mono-and bispecific therapeutic antibodies. Ligand has established multiple alliances, licenses and other business relationships with the world's leading pharmaceutical companies including Novartis, Amgen, Merck, Pfizer, Celgene, Gilead, Janssen, Baxter International and Eli Lilly. This news release contains forward-looking statements by Ligand that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. Actual events or results may differ from our expectations. For example, there can be no assurances that Ligand will be able to develop a next-generation OmniAb technology or that the antibody treatments will continue to be the fastest-growing segment of the pharmaceutical industry. The failure to meet expectations with respect to any of the foregoing matters may reduce Ligand's stock price. Additional information concerning these and other important risk factors affecting Ligand can be found in Ligand's prior press releases available at www.ligand.com as well as in Ligand's public periodic filings with the Securities and Exchange Commission, available at www.sec.gov. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this press release, except as required by law. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.
News Article | February 15, 2017
Multi-drug resistance in bacteria has been identified as a major worldwide public health concern by the World Health Organization. Multi-drug resistant bacteria are responsible for approximately 700,000 deaths per year, a figure which the WHO says could reach 10 million by the year 2050. EptA causes multi-drug resistance by masking bacteria against both the human immune system and important classes of antibiotics. A very similar variant of EptA called MCR-1 was discovered in 2015 causing resistance to colistin, a last resort antibiotic for bacteria untreatable by other means. Alarmingly, MCR-1 is not limited to a single type of bacteria, but is able to spread between different species of bacteria increasing its harmfullness significantly. Lead scientist in the study, Professor of Structural Biology Alice Vrielink from UWA's School of Molecular Sciences, said the researchers used a technique called X-ray crystallography to map three-dimensional shape of EptA. "The function of a protein molecule is directly related to it's three-dimensional shape," Professor Vrielink said. "This new knowledge of the shape and unique structure of EptA (and MCR-1) will help scientists develop an effective treatment to prevent antibiotic resistance of these super bugs, a huge step forward for global health." Work towards identifying potential new therapuetic molecules targeting EptA and MCR-1 is already underway through joint efforts by researchers at the UWA School of Molecular Sciences, the Marshall Center for Infectious Disease and the Monash Institute of Pharmaceutical Sciences. The research is funded by National Health and Medical Research Council of Australia and included collaborations from several universities and organisations around the globe. The research has been published in the journal Proceedings of the National Academy of Sciences (PNAS). Explore further: Antibiotics can still kill drug-resistant bacteria if they 'push' hard enough into bacterial cells More information: Anandhi Anandan et al. Structure of a lipid A phosphoethanolamine transferase suggests how conformational changes govern substrate binding, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1612927114
Spurlino J.C.,Structural Biology
Methods in Enzymology | Year: 2011
Abstract We screen for fragments using X-ray crystallography as the primary screen. There are several unique features in our screening methodology. As a result of using X-ray diffraction as our primary screen, we do not use affinity data to bias our data collection or design in progressing hits toward a lead. Another difference in our methodology is that we choose to group our compounds as shape-similar groups. We also screen in a first pass mode without recollecting failed diffraction experiments. This method of screening results in an average loss of 510% of the data sets for the primary screen. The remaining data sets offer enough information to successfully advance three to five scaffolds into the secondary library design. We do not deconvolute the wells which show evidence of fragment binding by repeating the soaks with single compounds. Instead, evaluation of the possible fragments is done by refinement and examination of the resulting electron density difference maps. These methods allow us to complete the initial screen of a primary library of fragments in less than 3 months. A secondary library of fragments is designed using the base structures with electron density envelopes from the successful fragment hits of the primary library. Chemistry is chosen to probe interactions with the target and push the observed binding pocket limits in order to more clearly define the plasticity and range of possible extensions to the scaffolds chosen. The secondary library compounds are also screened in shape-similar groupings of five that are chosen without the knowledge of binding affinity. Our approach is a completely orthogonal one from traditional high-throughput screening in finding novel compounds. © 2011 Elsevier Inc.
News Article | March 15, 2016
Enrico Di Cera, M.D., chair of biochemistry and molecular biology at Saint Louis University, is an author on the paper and says that the Structural Biology Grid Consortium has developed a repository, the Structural Biology Data Grid, to deposit, search and download structural biology data sets. In the current study, researchers found that the repository was effective in allowing researchers to reproduce earlier findings, letting work in the field progress. "This is a transformative development in the field," said Di Cera. "Finally, we may take full advantage of the enormous amounts of data being generated by structural biologists." X-ray crystallography, one of the most powerful tools in structural biology, allows researchers to determine the structure of proteins, nucleic acids and other small molecules at atomic level resolution. Understanding a protein's structure opens the door to understanding the molecular basis of diseases and developing new therapeutic strategies of intervention. Crystallographers share their findings in academic journals and currently use standard repositories of processed datasets like the Protein Data Bank. The Structural Biology Data Grid supports archiving of raw experimental datasets using a distribution model of computing clusters. Benefits include rapid access of the original experimental data for general use and validation. With the data collection process becoming increasingly streamlined, archiving through the Structural Biology Data Grid will become mainstream. In order to better leverage the breakthrough findings coming out of laboratories around the world, structural biologists created the Structural Biology Grid Consortium. The consortium's strategies include: curating and supporting a collection of data processing software; managing raw, experimental data sets; establishing a publication system for data sets; and integrating the storage resources of multiple research groups and institutions. In the current study, researchers conducted a pilot study, analyzing data from the repository collection. They found that the repository was effective in allowing researchers to reprocess data from earlier experiments, offering the opportunity to reproduce earlier findings, improve existing models, and catch possible mistakes earlier. "The Grid started as a joint effort of top structural biology labs around the world. We are proud to be part of a great initiative that uses big data for the benefits of the entire scientific community," said Di Cera. More information: Peter A. Meyer et al. Data publication with the structural biology data grid supports live analysis, Nature Communications (2016). DOI: 10.1038/ncomms10882
News Article | November 11, 2016
New work by a team of researchers based at The Rockefeller University has determined the structure of one important component of the restrictive gate through which cargo, including genetic information in the form of RNA transcribed from DNA, must pass. The results were published November 10 in Cell. After cells make an RNA version of DNA, they must package it, and ship it through a portal known as the nuclear pore. Once on the other side, some of that packaging has to come off. "We already understood bits and pieces of this aspect of flux into and out of the nucleus, but not the complete picture," says co-corresponding author Brian T. Chait's Laboratory of Mass Spectrometry and Gaseous Ion Chemistry. "To better understand the end of RNA's journey through the pore, we examined the protein complex responsible for receiving RNA and helping to unwrap it," says co-corresponding author Michael P. Rout, head of the Laboratory of Cellular and Structural Biology. "Next, we determined how this structure attached to the rest of the nuclear pore." Scientists typically crystallize proteins in order to determine their structure. But that approach didn't work well for this component because it is relatively large and has flexible parts. So the team pieced a variety of data together as if assembling a jigsaw puzzle. They found that the core of the complex takes a triangular shape, shown in solid red in the image above. This triangle sits atop a Y-shaped piece, shown in lighter red, creating an arm that extends, cranelike, over the pore. This configuration came as a surprise; previously these proteins were thought to stick out further from the pore, like antennae. Although the team performed their research on yeast, their work likely has relevance for humans, who possess a similar protein complex. In humans, mutations that affect the complex, as well as other parts of the RNA-catching arm, have been linked to cancer and other diseases. This new blueprint may help to explain why these mutations are harmful, the researchers say. Explore further: Parasites reveal how evolution has molded an ancient nuclear structure More information: Javier Fernandez-Martinez et al. Structure and Function of the Nuclear Pore Complex Cytoplasmic mRNA Export Platform, Cell (2016). DOI: 10.1016/j.cell.2016.10.028