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991.
A missense mutation I148M in PNPLA3 (patatin‐like phospholipase domain‐containing 3 protein) is significantly correlated with nonalcoholic fatty liver disease (NAFLD). To glean insights into mutation's effect on enzymatic activity, we performed molecular dynamics simulation and flexible docking studies. Our data show that the size of the substrate‐access entry site is significantly reduced in mutants, which limits the access of palmitic acid to the catalytic dyad. Besides, the binding free energy calculations suggest low affinity for substrate to mutant enzyme. The substrate‐bound system simulations reveal that the spatial arrangement of palmitic acid is distinct in wild‐type from that in mutant. The substrate recognition specificity is lost due to the loop where the I148M mutation was located. Our results provide strong evidence for the mechanism by which I148M affects the enzyme activity and suggest that mediating the dynamics may offer a potential avenue for NAFLD. Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
992.
Because of having many low molecular mass substrates, CYP2E1 is of particular interests to the pharmaceutical industry. Many evidences showed that this enzyme can adopt multiple substrates to significantly reduce the oxidation rate of the substrates. The detailed mechanism for this observation is still unclear. In the current study, we employed GPU‐accelerated molecular dynamics simulations to study the multiple‐binding mode of human CYP2E1, with an aim of offering a mechanistic explanation for the unexplained multiple‐substrate binding. Our results showed that Thr303 and Phe478 were key factors for the substrate recognition and multiple‐substrate binding. The former can form a significant hydrogen bond to recognize and position the substrate in the productive binding orientation in the active site. The latter acted as a mediator for the substrate communications via π–π stacking interactions. In the multiple‐binding mode, the aforementioned π–π stacking interactions formed by the aromatic rings of both substrates and Phe478 drove the first substrate far away from the catalytic center, orienting in an additional binding position and going against the substrate metabolism. All these findings could give atomic insights into the detailed mechanism for the multiple‐substrate binding in human CYP2E1, providing useful information for the drug metabolism mechanism and personalized use of clinical drugs. Proteins 2013; © 2012 Wiley Periodicals, Inc. 相似文献
993.
Biao Cheng Hao Gong Xiaochao Li Yue Sun Hong Chen Xin Zhang Qian Wu Ling Zheng Kun Huang 《Proteins》2013,81(4):613-621
The misfolding of human islet amyloid polypeptide (hIAPP) is regarded as one of the causative factors of type 2 diabetes mellitus (T2DM). Salvia miltiorrhiza (Danshen), one of the most commonly used of traditional Chinese medicines, is often used in Compound Recipes for treating diabetes, however with unclear mechanisms. Since salvianolic acid B (SalB) is the most abundant bioactive ingredient of salvia miltiorrhiza water‐extract. In this study, we tested whether SalB has any effect on the amyloidogenicity of hIAPP. Our results clearly suggest that SalB can significantly inhibit the formation of hIAPP amyloid and disaggregate hIAPP fibrils. Furthermore, photo‐crosslinking based oligomerization studies suggest SalB significantly suppresses the toxic oligomerization of hIAPP monomers. Cytotoxicity protection effects on pancreatic INS‐1 cells by SalB were also observed using MTT‐based assays, potentially due to the inhibition on the membrane disruption effects and attenuated mitochondria impairment induced by hIAPP. These results provide evidence that SalB may further be studied on the possible pharmacological treatment for T2DM. Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
994.
AbstractBiological contamination of surfaces in industry and healthcare is an important vector of disease transmission. Current assays for detecting surface-adherent contamination require extraction of biological soil. However, physical inaccessibility or poor solubility may limit recovery. Here, how the o-phthalaldehyde (OPA) protein assay can be modified to measure residual protein (modeled with bovine serum albumin) or biofilm on a surface without extraction is described. The assay limit of detection (LOD) for protein was 1.6 µg cm?2. The detection threshold for Staphylococcus epidermis biofilm was 117 µg cm?2. The clinical utility of the method was demonstrated for measurements taken from clinically used endoscopes. Since this method is more sensitive than extraction-based testing, clinical results should not be compared with conventional benchmarks. By enabling direct detection and quantification of soils in complex or hard-to-reach areas, this method has potential to improve the margin of safety in medical and industrial cleaning processes. 相似文献
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996.
Cation-induced conformational changes of peptide as a guide to developing insights into human diseases-related proteins have received a lot of attention. The interactions between poly-l-glutamate (PGA) and different cations, including Na+, K+ and Mg2+, respectively, are studied in solvent at a concentration of 1 M, and the behaviours of peptide with different cations are investigated. For Na+, an oscillatory stabilising process to α-helix PGA is found, in accordance with the uniform free-energy landscape, whereas for K+, an extended α-helix structure is formed by the terminal turns, suggesting a weaker attraction to charged head groups. For Mg2+, the bridged charged side chains are responsible for the maximum probability of helix state. These distinct structural changes can be attributed to the different interactions between charged head groups and cations. Both Na+ and K+ are mainly attracted around head groups by direct ion binding while Mg2+ is centrally trapped among adjacent charged head groups. In addition, a surprising shift of the backbone hydrogen bond, from intact state to intermediate state, is observed. This is opposite to the stabilising effect of Na+ around negatively charged head groups. 相似文献
997.
Bin Feng Jin-cheng Liu Jun Zhang Ken-ichi Ozaki Yan-yan Guo Ding-hua Yi Xiao-qiang Li Ming-gao Zhao 《Molecular neurobiology》2013,47(3):892-902
Motilin is a 22-amino-acid gastrointestinal polypeptide that was first isolated from the porcine intestine. We identified that motilin receptor is highly expressed in GABAergic interneurons in the basolateral nucleus (BLA) of the amygdala, the structure of which is closely involved in assigning stress disorder and anxiety. However, little is known about the role of motilin in BLA neuronal circuits and the molecular mechanisms of stress-related anxiety. Whole-cell recordings from amygdala slices showed that motilin depolarized the interneurons and facilitated GABAergic transmission in the BLA, which is mimicked by the motilin receptor agonist, erythromycin. BLA local injection of erythromycin or motilin can reduce the anxiety-like behavior in mice after acute stress. Therefore, motilin is essential in regulating interneuron excitability and GABAergic transmission in BLA. Moreover, the anxiolytic actions of motilin can partly be explained by modulating the BLA neuronal circuits. The present data demonstrate the importance of motilin in anxiety and the development of motilin receptor non-peptide agonist as a clear target for the potential treatment of anxiety disorders. 相似文献
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