The inhibitory mechanism of aurintricarboxylic acid targeting serine/threonine phosphatase Stp1 in Staphylococcus aureus: insights from molecular dynamics simulations

doi:10.1038/s41401-019-0216-x

	The inhibitory mechanism of aurintricarboxylic acid targeting serine/threonine phosphatase Stp1 in Staphylococcus aureus: insights from molecular dynamics simulations
	Liu, Ting-ting 1,2; Yang, Teng 3; Gao, Mei-na 1,2; Chen, Kai-xian 1,2; Yang, Song 3; Yu, Kun-qian 1,2; Jiang, Hua-liang 1,2,4
刊名	ACTA PHARMACOLOGICA SINICA
	2019-06-01
卷号	40 期号:6 页码:850-858
关键词	antimicrobial resistance Staphylococcus aureus serine/threonine phosphatase aurintricarboxylic acid molecular dynamics simulations flap subdomain
ISSN号	1671-4083
DOI	10.1038/s41401-019-0216-x
通讯作者	Yang, Song(jhzx.msm@gmail.com) ; Yu, Kun-qian(yukunqian@simm.ac.cn)
英文摘要	Serine/threonine phosphatase (Stp1) is a member of the bacterial Mg2+- or Mn2+- dependent protein phosphatase/protein phosphatase 2C family, which is involved in the regulation of Staphylococcus aureus virulence. Aurintricarboxylic acid (ATA) is a known Stp1 inhibitor with an IC50 of 1.03 mu M, but its inhibitory mechanism has not been elucidated in detail because the Stp1-ATA cocrystal structure has not been determined thus far. In this study, we performed 400 ns molecular dynamics (MD) simulations of the apo-Stp1 and Stp1-ATA complex models. During MD simulations, the flap subdomain of the Stp1-ATA complex experienced a clear conformational transition from an open state to a closed state, whereas the flap domain of apo-Stp1 changed from an open state to a semi-open state. In the Stp1-ATA complex model, the hydrogen bond (H-bond) between D137 and N142 disappeared, whereas critical H-bond interactions were formed between Q160 and H13, Q160/R161 and ATA, as well as N162 and D198. Finally, four residues (D137, N142, Q160, and R161) in Stp1 were mutated to alanine and the mutant enzymes were assessed using phosphate enzyme activity assays, which confirmed their important roles in maintaining Stp1 activity. This study indicated the inhibitory mechanism of ATA targeting Stp1 using MD simulations and sheds light on the future design of allosteric Stp1 inhibitors.
资助项目	National Key R & D Program of China[2016YFB0201700] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2018ZX09711003-003-005] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDC01040100]
WOS关键词	PROTEIN ; DOCKING ; VIRULENCE ; PHOSPHORYLATION ; VANCOMYCIN ; RESISTANCE ; PARADIGM ; GLIDE
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000469208200014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289682]
专题	中国科学院上海药物研究所
通讯作者	Yang, Song; Yu, Kun-qian
作者单位	1.Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Guizhou Univ, State Key Lab Breeding Base Green Pesticide & Agr, Key Lab Green Pesticide & Agr Bioengn, Ctr R&D Fine Chem,Minist Educ, Guiyang 550025, Guizhou, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Materia Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Liu, Ting-ting,Yang, Teng,Gao, Mei-na,et al. The inhibitory mechanism of aurintricarboxylic acid targeting serine/threonine phosphatase Stp1 in Staphylococcus aureus: insights from molecular dynamics simulations[J]. ACTA PHARMACOLOGICA SINICA,2019,40(6):850-858.
APA	Liu, Ting-ting.,Yang, Teng.,Gao, Mei-na.,Chen, Kai-xian.,Yang, Song.,...&Jiang, Hua-liang.(2019).The inhibitory mechanism of aurintricarboxylic acid targeting serine/threonine phosphatase Stp1 in Staphylococcus aureus: insights from molecular dynamics simulations.ACTA PHARMACOLOGICA SINICA,40(6),850-858.
MLA	Liu, Ting-ting,et al."The inhibitory mechanism of aurintricarboxylic acid targeting serine/threonine phosphatase Stp1 in Staphylococcus aureus: insights from molecular dynamics simulations".ACTA PHARMACOLOGICA SINICA 40.6(2019):850-858.