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首页> 外文期刊>Biochemistry >Allosteric Regulation of Glycogen Synthase Kinase 3β: A Theoretical Study
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Allosteric Regulation of Glycogen Synthase Kinase 3β: A Theoretical Study

机译：糖原合酶激酶3β的变构调控：理论研究

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摘要

Glycogen synthase kinase 3β (GSK-3β) is a serine-threonine kinase belonging to the CMGCnfamily that plays a key role in many biological processes, such as glucose metabolism, cell cycle regulation,nand proliferation. Like most protein kinases, GSK-3β is regulated via multiple pathways and sites. Wenperformed all-atom molecular dynamics simulations on the unphosphorylated and phosphorylated unboundnGSK-3β and the phosphorylated GSK-3β bound to a peptide substrate, its product, and a derived inhibitor.nWe found that GSK-3β autophosphorylation at residue Tyrn216nresults in widening of the catalytic groove,nthereby facilitating substrate access. In addition, we studied the interactions of the phosphorylated GSK-3βnwith a substrate and peptide inhibitor located at the active site and observed higher affinity of the inhibitor tonthe kinase. Furthermore, we detected a potential remote binding site which was previously identified in othernkinases. In agreement with experiments we observed that binding of specific peptides at this remote site leadsnto stabilization of the activation loop located in the active site. We speculate that this stabilization couldnenhance the catalytic activity of the kinase. We point to this remote site as being structurally conserved andnsuggest that the allosteric phenomenon observed here may occur in the protein kinase superfamily.
机译：糖原合酶激酶3β（GSK-3β）是属于CMGC家族的丝氨酸-苏氨酸激酶，在许多生物过程中起着关键作用，例如葡萄糖代谢，细胞周期调节，自然增殖。像大多数蛋白激酶一样，GSK-3β通过多种途径和位点调控。 Wen对未磷酸化和磷酸化的未结合nGSK-3β和磷酸化的GSK-3β结合到肽底物，其产物和衍生的抑制剂上进行了全原子分子动力学模拟.n我们发现残基Tyrn216上的GSK-3β自磷酸化导致催化作用的加宽凹槽，从而方便了基板的进入。另外，我们研究了磷酸化的GSK-3βn与位于活性位点的底物和肽抑制剂的相互作用，并观察到该抑制剂与该激酶的亲和力更高。此外，我们检测到了以前在其他激酶中鉴定出的潜在的远程结合位点。与实验一致，我们观察到在该远端位点的特异性肽的结合导致位于活性位点的激活环的稳定。我们推测这种稳定化可以增强激酶的催化活性。我们指出此远程站点在结构上是保守的，这暗示此处观察到的变构现象可能发生在蛋白激酶超家族中。

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  • 来源
    《Biochemistry》 |2010年第51期|p.10890-10901|共12页
  • 作者

    Idit Buch Dan Fishelovitch Nir London Barak Raveh Haim J. Wolfson and Ruth Nussinov;

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    ‡Department of Human Molecular Genetics and Biochemistry, Sackler Institute of Molecular Medicine,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel,§Department of Microbiology and Molecular Genetics,Institute for Medical Research IMRIC, Faculty of Medicine, Hadassah Medical School, The Hebrew University, POB 12272,Jerusalem 91120, Israel,) School of Computer Science, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University,TelAviv69978,Israel,and ^SAIC-Frederick, Inc., Center for Cancer Research Nanobiology Program, NCI;

    Frederick,Frederick, Maryland 21702, United States;

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