Conformational Dynamics of Response Regulator RegX3 from Mycobacterium tuberculosis.
Conformational Dynamics of Response Regulator RegX3 from Mycobacterium tuberculosis.
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结核分枝杆菌反应调节因子 RegX3 的构象动力学
DOI：
10.1371/journal.pone.0133389
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Han A
中科院分区：
文献类型：
--
作者：
Ahmad A;Cai Y;Chen X;Shuai J;Han A
双组分信号转导系统（TCS）是细菌、真菌甚至植物对各种环境胁迫的适应性反应的重要组成部分。TCS通常由传感器组氨酸激酶（SK）及其同源应答调节因子（RR）组成，其通常具有两个结构域-N末端受体结构域（RD）和C末端效应器结构域（艾德）。组氨酸激酶通过促进二聚化使RD磷酸化以激活艾德。然而，尽管在结构研究方面取得了重大进展，但RR如何将激活信号从RD传递到艾德仍然是一个谜。本文以结核分枝杆菌RegX 3的活性构象为模型系统，通过计算方法分析了OmpR/PhoB家族的活性到非活性的转变过程。从150 ns分子动力学模拟产生的RegX 3的非活性状态具有通常在非活性RR中保守的Thr 79和Tyr 98的旋转异构体构象。β4α4环中的Arg 81与β1α1环协同作用，在活性到非活性转变期间改变其相互作用伙伴，可能导致RegX 3螺旋α1的N末端移动。RegX 3的整体构象动力学主要依赖于α4β5区域，尤其是7个热点残基（Tyr 98至Ser 104），在其附近的二聚体界面上的几个共进化残基，包括Ile 76-Asp 96，Asp 97-Arg 111和Glu 24-Arg 113对，对信号转导至关重要。总之，我们的计算分析表明，在RR活性到非活性状态转变期间，Asp磷酸化、近端环和α4β5α5二聚体界面之间存在分子联系，这通常不能从静态晶体结构中明确定义。
Two-component signal transduction systems (TCS) are vital for adaptive responses to various environmental stresses in bacteria, fungi and even plants. A TCS typically comprises of a sensor histidine kinase (SK) with its cognate response regulator (RR), which often has two domains—N terminal receiver domain (RD) and C terminal effector domain (ED). The histidine kinase phosphorylates the RD to activate the ED by promoting dimerization. However, despite significant progress on structural studies, how RR transmits activation signal from RD to ED remains elusive. Here we analyzed active to inactive transition process of OmpR/PhoB family using an active conformation of RegX3 from Mycobacterium tuberculosis as a model system by computational approaches. An inactive state of RegX3 generated from 150 ns molecular dynamic simulation has rotameric conformations of Thr79 and Tyr98 that are generally conserved in inactive RRs. Arg81 in loop β4α4 acts synergistically with loop β1α1 to change its interaction partners during active to inactive transition, potentially leading to the N-terminal movement of RegX3 helix α1. Global conformational dynamics of RegX3 is mainly dependent on α4β5 region, in particular seven ‘hot-spot’ residues (Tyr98 to Ser104), adjacent to which several coevolved residues at dimeric interface, including Ile76-Asp96, Asp97-Arg111 and Glu24-Arg113 pairs, are critical for signal transduction. Taken together, our computational analyses suggest a molecular linkage between Asp phosphorylation, proximal loops and α4β5α5 dimeric interface during RR active to inactive state transition, which is not often evidently defined from static crystal structures.