Mishra Ashwini K, Lambright David G
Program in Molecular Medicine and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, 01605.
Biopolymers. 2016 Aug;105(8):431-48. doi: 10.1002/bip.22833.
Widespread utilization of small GTPases as major regulatory hubs in many different biological systems derives from a conserved conformational switch mechanism that facilitates cycling between GTP-bound active and GDP-bound inactive states under control of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), which accelerate slow intrinsic rates of activation by nucleotide exchange and deactivation by GTP hydrolysis, respectively. Here we review developments leading to current understanding of intrinsic and GAP catalyzed GTP hydrolytic reactions in small GTPases from structural, molecular and chemical mechanistic perspectives. Despite the apparent simplicity of the GTPase cycle, the structural bases underlying the hallmark hydrolytic reaction and catalytic acceleration by GAPs are considerably more diverse than originally anticipated. Even the most fundamental aspects of the reaction mechanism have been challenging to decipher. Through a combination of experimental and in silico approaches, the outlines of a consensus view have begun to emerge for the best studied paradigms. Nevertheless, recent observations indicate that there is still much to be learned. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 431-448, 2016.
小GTP酶作为许多不同生物系统中的主要调节枢纽被广泛利用，这源于一种保守的构象开关机制，该机制在鸟嘌呤核苷酸交换因子（GEFs）和GTP酶激活蛋白（GAPs）的控制下，促进GTP结合的活性状态和GDP结合的非活性状态之间的循环，它们分别通过核苷酸交换加速缓慢的内在激活速率和通过GTP水解加速失活速率。在这里，我们从结构、分子和化学机制的角度回顾了导致目前对小GTP酶中内在的和GAP催化的GTP水解反应理解的进展。尽管GTP酶循环表面上很简单，但标志性水解反应和GAP催化加速的结构基础比最初预期的要多样化得多。即使是反应机制中最基本的方面也难以破译。通过实验和计算机方法的结合，对于研究最深入的范例，一种共识观点的轮廓已经开始出现。然而，最近的观察表明仍有许多有待了解的地方。© 2016威利期刊公司。生物聚合物105: 431 - 448，2016。
