Structural basis of DNA sequence recognition by the response regulator PhoP in Mycobacterium tuberculosis.
Structural basis of DNA sequence recognition by the response regulator PhoP in Mycobacterium tuberculosis.
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DOI：
10.1038/srep24442
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发表时间：
2016-04-15
影响因子：
4.6
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
He X;Wang L;Wang S
PhoP转录调控因子是结核分枝杆菌的重要毒力因子，是开发新型抗结核药物和减毒结核疫苗的靶点。PhoP通过识别具有4-bp间隔区的7-bp基序的直接重复序列作为高度合作的二聚体与DNA结合。为了阐明PhoP-DNA结合机制，我们测定了PhoP-DNA复合物的晶体结构。该结构揭示了一个串联的PhoP二聚体，结合到直接重复。令人惊讶的串联排列的接收器域允许的四个域的PhoP二聚体形成一个紧凑的结构，占一个4-bp的间隔区的严格要求和二聚体的高度合作的结合。PhoP-DNA相互作用仅涉及效应结构域。序列识别螺旋与大沟中的7-bp基序的碱基接触，翼与相邻的小沟相互作用。该结构为阐明PhoP调节M毒力的机制提供了一个起点。结核病和指导PhoP抑制剂筛选平台的设计。
The transcriptional regulator PhoP is an essential virulence factor in Mycobacterium tuberculosis, and it presents a target for the development of new anti-tuberculosis drugs and attenuated tuberculosis vaccine strains. PhoP binds to DNA as a highly cooperative dimer by recognizing direct repeats of 7-bp motifs with a 4-bp spacer. To elucidate the PhoP-DNA binding mechanism, we determined the crystal structure of the PhoP-DNA complex. The structure revealed a tandem PhoP dimer that bound to the direct repeat. The surprising tandem arrangement of the receiver domains allowed the four domains of the PhoP dimer to form a compact structure, accounting for the strict requirement of a 4-bp spacer and the highly cooperative binding of the dimer. The PhoP-DNA interactions exclusively involved the effector domain. The sequence-recognition helix made contact with the bases of the 7-bp motif in the major groove, and the wing interacted with the adjacent minor groove. The structure provides a starting point for the elucidation of the mechanism by which PhoP regulates the virulence of M. tuberculosis and guides the design of screening platforms for PhoP inhibitors.