Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO

doi:10.1016/j.jmb.2020.05.019

	Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO
	Yang, Xiaolin1,2,3,8 ; Hu, Tianyu1,2 ; Yang, Xiuna1,2 ; Xu, Wenqing1,2 ; Yang, Haitao1,2 ; Guddat, Luke W.7; Zhang, Bing1,2 ; Rao, Zihe1,2,4,5,6
	2020-07-24
发表期刊	JOURNAL OF MOLECULAR BIOLOGY (IF:4.7[JCR-2023],4.9[5-Year])
ISSN	0022-2836
EISSN	1089-8638
卷号	432 期号:16 页码:4426-4434
发表状态	已发表
DOI	10.1016/j.jmb.2020.05.019
摘要	Novel antitubercular agents are urgently needed to combat the emergence of global drug resistance to human tuberculosis. Mycobacterial membrane protein Large 3 (MmpL3) is a promising drug target because its activity is essential and required for cell-wall biosynthesis. Several classes of MmpL3 inhibitors have been developed against Mycobacterium tuberculosis (Mtb) with potent anti-tuberculosis activity. These include the drug candidate SQ109, which has progressed to phase IIb/III clinical trials. Here, we have determined the crystal structures of MmpL3 in complex with NITD-349 and SPIRO. Both inhibitors bind deep in the central channel of transmembrane domain and cause conformational changes to the protein. The amide nitrogen and indole nitrogen of NITD-349 and the piperidine nitrogen of SPIRO interact and clamp Asp645. Structural analysis of the two structures reveals that these inhibitors target the proton relay pathway to block the activity of MmpL3. The findings presented here enrich our understanding of the binding modes of MmpL3 inhibitors and provide directions to enable further rational drug design targeting MmpL3. (C) 2020 Elsevier Ltd. All rights reserved.
关键词	Mycobacterium tuberculosis mycobacterial membrane protein Large MmpL3 NITD-349 SPIRO
收录类别	SCI ; SCIE
语种	英语
资助项目	National Key Research and Development Program of China[2017YFC0840300] ; National Natural Science Foundation of China[81520108019]
WOS研究方向	Biochemistry & Molecular Biology
WOS类目	Biochemistry & Molecular Biology
WOS记录号	WOS:000552832700007
出版者	ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
WOS关键词	MYCOLIC ACID TRANSPORT ; MEMBRANE TRANSPORTER ; DRUG DISCOVERY ; INDOLE-2-CARBOXAMIDES ; IDENTIFICATION ; MECHANISM ; ENVELOPE ; FAMILY ; TARGET ; MODEL
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/122703
专题	生命科学与技术学院_PI研究组_许文青组免疫化学研究所_特聘教授组_饶子和组生命科学与技术学院_硕士生生命科学与技术学院_博士生免疫化学研究所_PI研究组_杨海涛组
通讯作者	Zhang, Bing
作者单位	1.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China 4.Nankai Univ, State Key Lab Med Chem Biol, Tianjin 300353, Peoples R China 5.Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China 6.Tsinghua Univ, Lab Struct Biol, Beijing 100084, Peoples R China 7.Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia 8.Univ Chinese Acad Sci, Beijing 100101, Peoples R China
第一作者单位	免疫化学研究所; 生命科学与技术学院
通讯作者单位	免疫化学研究所; 生命科学与技术学院
第一作者的第一单位	免疫化学研究所
推荐引用方式 GB/T 7714	Yang, Xiaolin,Hu, Tianyu,Yang, Xiuna,et al. Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO[J]. JOURNAL OF MOLECULAR BIOLOGY,2020,432(16):4426-4434.
APA	Yang, Xiaolin.,Hu, Tianyu.,Yang, Xiuna.,Xu, Wenqing.,Yang, Haitao.,...&Rao, Zihe.(2020).Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO.JOURNAL OF MOLECULAR BIOLOGY,432(16),4426-4434.
MLA	Yang, Xiaolin,et al."Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO".JOURNAL OF MOLECULAR BIOLOGY 432.16(2020):4426-4434.