Structural analysis of the regulatory mechanism of MarR protein Rv2887 in M. tuberculosis

Abstract MarR family proteins are transcriptional regulators that control expression of bacterial proteins involved in metabolism, virulence, stress responses and multi-drug resistance, mainly via ligand-mediated attenuation of DNA binding. Greater understanding of their underlying regulatory mechan...

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Autores principales:	Yun-Rong Gao, De-Feng Li, Joy Fleming, Ya-Feng Zhou, Ying Liu, Jiao-Yu Deng, Lin Zhou, Jie Zhou, Guo-Feng Zhu, Xian-En Zhang, Da-Cheng Wang, Li-Jun Bi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ab64271858cf4dd0aaa77d7912221b43
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spelling	oai:doaj.org-article:ab64271858cf4dd0aaa77d7912221b432021-12-02T15:05:44ZStructural analysis of the regulatory mechanism of MarR protein Rv2887 in M. tuberculosis10.1038/s41598-017-01705-42045-2322https://doaj.org/article/ab64271858cf4dd0aaa77d7912221b432017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01705-4https://doaj.org/toc/2045-2322Abstract MarR family proteins are transcriptional regulators that control expression of bacterial proteins involved in metabolism, virulence, stress responses and multi-drug resistance, mainly via ligand-mediated attenuation of DNA binding. Greater understanding of their underlying regulatory mechanism may open up new avenues for the effective treatment of bacterial infections. To gain molecular insight into the mechanism of Rv2887, a MarR family protein in M. tuberculosis, we first showed that it binds salicylate (SA) and para-aminosalicylic acid (PAS), its structural analogue and an antitubercular drug, in a 1:1 stoichiometry with high affinity. Subsequent determination and analysis of Rv2887 crystal structures in apo form, and in complex with SA, PAS and DNA showed that SA and PAS bind to Rv2887 at similar sites, and that Rv2887 interacts with DNA mainly by insertion of helix α4 into the major groove. Ligand binding triggers rotation of the wHTH domain of Rv2887 toward the dimerization domain, causing changes in protein conformation such that it can no longer bind to a 27 bp recognition sequence in the upstream region of gene Rv0560c. The structures provided here lay a foundation for the design of small molecules that target Rv2887, a potential new approach for the development of anti-mycobacterials.Yun-Rong GaoDe-Feng LiJoy FlemingYa-Feng ZhouYing LiuJiao-Yu DengLin ZhouJie ZhouGuo-Feng ZhuXian-En ZhangDa-Cheng WangLi-Jun BiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yun-Rong Gao De-Feng Li Joy Fleming Ya-Feng Zhou Ying Liu Jiao-Yu Deng Lin Zhou Jie Zhou Guo-Feng Zhu Xian-En Zhang Da-Cheng Wang Li-Jun Bi Structural analysis of the regulatory mechanism of MarR protein Rv2887 in M. tuberculosis
description	Abstract MarR family proteins are transcriptional regulators that control expression of bacterial proteins involved in metabolism, virulence, stress responses and multi-drug resistance, mainly via ligand-mediated attenuation of DNA binding. Greater understanding of their underlying regulatory mechanism may open up new avenues for the effective treatment of bacterial infections. To gain molecular insight into the mechanism of Rv2887, a MarR family protein in M. tuberculosis, we first showed that it binds salicylate (SA) and para-aminosalicylic acid (PAS), its structural analogue and an antitubercular drug, in a 1:1 stoichiometry with high affinity. Subsequent determination and analysis of Rv2887 crystal structures in apo form, and in complex with SA, PAS and DNA showed that SA and PAS bind to Rv2887 at similar sites, and that Rv2887 interacts with DNA mainly by insertion of helix α4 into the major groove. Ligand binding triggers rotation of the wHTH domain of Rv2887 toward the dimerization domain, causing changes in protein conformation such that it can no longer bind to a 27 bp recognition sequence in the upstream region of gene Rv0560c. The structures provided here lay a foundation for the design of small molecules that target Rv2887, a potential new approach for the development of anti-mycobacterials.
format	article
author	Yun-Rong Gao De-Feng Li Joy Fleming Ya-Feng Zhou Ying Liu Jiao-Yu Deng Lin Zhou Jie Zhou Guo-Feng Zhu Xian-En Zhang Da-Cheng Wang Li-Jun Bi
author_facet	Yun-Rong Gao De-Feng Li Joy Fleming Ya-Feng Zhou Ying Liu Jiao-Yu Deng Lin Zhou Jie Zhou Guo-Feng Zhu Xian-En Zhang Da-Cheng Wang Li-Jun Bi
author_sort	Yun-Rong Gao
title	Structural analysis of the regulatory mechanism of MarR protein Rv2887 in M. tuberculosis
title_short	Structural analysis of the regulatory mechanism of MarR protein Rv2887 in M. tuberculosis
title_full	Structural analysis of the regulatory mechanism of MarR protein Rv2887 in M. tuberculosis
title_fullStr	Structural analysis of the regulatory mechanism of MarR protein Rv2887 in M. tuberculosis
title_full_unstemmed	Structural analysis of the regulatory mechanism of MarR protein Rv2887 in M. tuberculosis
title_sort	structural analysis of the regulatory mechanism of marr protein rv2887 in m. tuberculosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ab64271858cf4dd0aaa77d7912221b43
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_version_	1718388724281114624

Structural analysis of the regulatory mechanism of MarR protein Rv2887 in M. tuberculosis

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