Structural basis of rifampin inactivation by rifampin phosphotransferase

doi:10.1073/pnas.1523614113

	Structural basis of rifampin inactivation by rifampin phosphotransferase
	Qi, Xiaofeng 1,5; Lin, Wei 4,5; Ma, Miaolian 5; Wang, Chengyuan 1,5; He, Yang 1,5; He, Nisha 1,3; Gao, Jing 2; Zhou, Hu2 ; Xiao, Youli 3; Wang, Yong 3
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2016-04-05
卷号	113 期号:14 页码:3803-3808
关键词	antibiotic resistance rifampin phosphotransferase molecular mechanism toggle switch
ISSN号	0027-8424
DOI	10.1073/pnas.1523614113
文献子类	Article
英文摘要	Rifampin (RIF) is a first-line drug used for the treatment of tuberculosis and other bacterial infections. Various RIF resistance mechanisms have been reported, and recently an RIF-inactivation enzyme, RIF phosphotransferase ( RPH), was reported to phosphorylate RIF at its C21 hydroxyl at the cost of ATP. However, the underlying molecular mechanism remained unknown. Here, we solve the structures of RPH from Listeria monocytogenes ( LmRPH) in different conformations. LmRPH comprises three domains: an ATP-binding domain ( AD), an RIF-binding domain ( RD), and a catalytic His-containing domain ( HD). Structural analyses reveal that the C-terminal HD can swing between the AD and RD, like a toggle switch, to transfer phosphate. In addition to its catalytic role, the HD can bind to the AD and induce conformational changes that stabilize ATP binding, and the binding of the HD to the RD is required for the formation of the RIF-binding pocket. A line of hydrophobic residues forms the RIF-binding pocket and interacts with the 1-amino, 2-naphthol, 4-sulfonic acid and naphthol moieties of RIF. The R group of RIF points toward the outside of the pocket, explaining the low substrate selectivity of RPH. Four residues near the C21 hydroxyl of RIF, His825, Arg666, Lys670, and Gln337, were found to play essential roles in the phosphorylation of RIF; among these the His825 residue may function as the phosphate acceptor and donor. Our study reveals the molecular mechanism of RIF phosphorylation catalyzed by RPH and will guide the development of a new generation of rifamycins.
资助项目	National Natural Science Foundation of China[31322016] ; National Program on Key Basic Research Projects Grant[2015CB910900] ; National Key Laboratory of Plant Molecular Genetics[00000000] ; CAS Center for Excellence in Molecular Plant Sciences[00000000] ; Institute of Plant Physiology and Ecology[00000000] ; Shanghai Institutes for Biological Sciences, CAS[00000000]
WOS关键词	PYRUVATE PHOSPHATE DIKINASE ; SWIVELING-DOMAIN MECHANISM ; RESISTANCE ; IDENTIFICATION ; TUBERCULOSIS ; ANTIBIOTICS ; INFECTIONS ; DIVERSITY ; RIFAXIMIN
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATL ACAD SCIENCES
WOS记录号	WOS:000373354000044
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276080]
专题	分析化学研究室
通讯作者	Zhang, Peng
作者单位	1.Univ Chinese Acad Sci, Beijing 100039, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Synthet Biol, Ctr Excellence Mol Plant Sci,Inst Plant Physiol &, Shanghai 200032, Peoples R China; 4.Rutgers State Univ, Waksman Inst Microbiol, Piscataway, NJ 08854 USA 5.Chinese Acad Sci, Shanghai Inst Biol Sci, Natl Key Lab Plant Mol Genet, Ctr Excellence Mol Plant Sci,Inst Plant Physiol &, Shanghai 200032, Peoples R China;
推荐引用方式 GB/T 7714	Qi, Xiaofeng,Lin, Wei,Ma, Miaolian,et al. Structural basis of rifampin inactivation by rifampin phosphotransferase[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2016,113(14):3803-3808.
APA	Qi, Xiaofeng.,Lin, Wei.,Ma, Miaolian.,Wang, Chengyuan.,He, Yang.,...&Zhang, Peng.(2016).Structural basis of rifampin inactivation by rifampin phosphotransferase.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,113(14),3803-3808.
MLA	Qi, Xiaofeng,et al."Structural basis of rifampin inactivation by rifampin phosphotransferase".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113.14(2016):3803-3808.