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Structural basis of rifampin inactivation by rifampin phosphotransferase

文献类型：期刊论文

作者Qi, Xiaofeng1,5; Lin, Wei4,5; Ma, Miaolian5; Wang, Chengyuan1,5; He, Yang1,5; He, Nisha1,3; Gao, Jing2; Zhou, Hu2; Xiao, Youli3; Wang, Yong3
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期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
DOI10.1073/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.
WOS关键词PYRUVATE PHOSPHATE DIKINASE ; SWIVELING-DOMAIN MECHANISM ; RESISTANCE ; IDENTIFICATION ; TUBERCULOSIS ; ANTIBIOTICS ; INFECTIONS ; DIVERSITY ; RIFAXIMIN
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研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000373354000044
出版者NATL ACAD SCIENCES
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.

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来源：上海药物研究所

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