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Zhao Q.,Liaoning University | Zhao Q.,Research Center for Computer Simulating and Information Processing of Bio macromolecules of Liaoning Province | Yao C.-G.,Shaoxing University | Tang J.,China University of Mining and Technology | Liu L.-W.,Dalian Jiaotong University
Frontiers of Physics | Year: 2016

Bistable switch modules are among the most important fundamental motifs in signal-transduction pathways. To better understand their spatial signal transduction, we model the diffusion process in the one-dimensional (1–D) domain. We find that when none of the elements diffuse, the response of the system exhibits a spatial switch–like property. However, when one of the elements is highly diffusible, the response of the system does not show any spatial switching behavior. Furthermore, we observe that the spatial responses of the system are more sensitive to the time constant of the switch when none of the elements are diffusible. Further, a slow loop keeps the system in the high steady state more positions than that in the fast loop. Finally, we consolidate our numerical results analytically by performing a mathematical method. © 2016, Higher Education Press and Springer-Verlag Berlin Heidelberg.

Quan X.,Liaoning University | Chen X.,Liaoning University | Sun D.,Liaoning University | Xu B.,Liaoning University | And 6 more authors.
Journal of Molecular Modeling | Year: 2016

DHCR24 encodes 3β-hydroxysterol-Δ24-reductase (DHCR24) catalyzing the cholesterol synthesis from desmosterol using the flavin adenine dinucleotide (FAD) as a co-factor. It is generally accepted that U18666a inhibits the reductase activity of DHCR24, but the detailed mechanism remains elusive. To explore the mechanism of the inhibitory effect of U18666a on DHCR24, we performed molecular dynamics (MD) simulations of two complexes including complexes of DHCR24-FAD-desmosterol enzymatic reactive components with and without the inhibitor U18666a. We found that the U18666a bound into the hydrophobic package near the FAD package of DHCR24. Furthermore, binding free energy of DHCR24 and desmosterol without U18666a is −54.86 kcal/mol, while the system with U18666a is −62.23 kcal/mol, suggesting that the affinity of the substrate desmosterol to DHCR24 was increased in response to the U18666a. In addition, U18666a interacts with FAD by newly forming three hydrogen bonds with Lys292, Lys367, and Gly438 of DHCR24. Finally, secondary structural analysis data obtained from the surrounding hot spots showed that U18666a induced dramatic secondary structural changes around the key residues in the interaction of DHCR24, FAD, and desmosterol. Taken together, these results for the first time demonstrate at the molecular structure level that U18666a blocks DHCR24 activity through an allosteric inhibiting mechanism, which may provide new insight into the development of a new type of cholesterol-lowering drug targeting to block the activity of DHCR24. © 2016, Springer-Verlag Berlin Heidelberg.

Lu X.,Liaoning University | Sun D.,Liaoning University | Xu B.,Liaoning University | Pan J.,Shenyang Medical College | And 5 more authors.
Journal of Urology | Year: 2016

Purpose: SLC26A6 is a multifunctional anion transporter with a critical physiological role in the transport of oxalate anions. Recognizing a genetic variant of SLC26A6 would advance our understanding of oxalate transport in the formation of calcium oxalate stones. Materials and Methods: All nsSNPs (nonsynonymous single nucleotide polymorphisms) reported in human SLC26A6 were investigated using 4 in silico tools, including SIFT (Sorting Intolerant From Tolerant), PROVEAN (Protein Variation Effect Analyzer), PhD-SNP (Predictor of human Deleterious Single Nucleotide Polymorphisms) and MutPred. A total of 426 subjects, including 225 with kidney stones and 201 healthy controls, were included in study to genotype the candidate disease associated nsSNP using allele specific polymerase chain reaction. Furthermore, the structural consequences due to the mutation were assessed using homology modeling and molecular dynamics simulation methods. Results: The nsSNP rs184187143 was identified as a more probable disease associated variant in the SLC26A6 gene by in silico screening. The C allele carrier showed a 6.1-fold increased kidney stone risk compared with G allele carriers in the nsSNP (OR 6.1, 95% CI 1.36-27.38, p = 0.007). We found that the mutation from arginine to glycine leads to the loss of 2 hydrogen bonds and to an unstable structure in the STAS domain of SLC26A6. Conclusions: Our results indicate that the variant G539R in the SLC26A6 gene is associated with kidney stone risk, providing a clear clue to further achieve insight into oxalate transport in kidney stone formation. © 2016 American Urological Association Education and Research, Inc.

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