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Conformation and dynamics of the C-terminal region in human phosphoglycerate mutase 1

文献类型：期刊论文

作者Liu, Shi-en1,2; Hu, Jun-chi1,2; Zhang, Hao1,2; Xu, Pan1,2; Wan, Wei1,2; Zheng, Ming-yue1,2; Yu, Kun-qian1,2; Ding, Hong2; Jiang, Hua-liang1,2; Zhou, Lu3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2017-12
卷号38期号:12页码:1673-1682
ISSN号1671-4083
关键词phosphoglycerate mutase 1 (PGAM1) human cancers metabolic target C-terminal region conformational changes molecular dynamics simulation
DOI10.1038/aps.2017.37
文献子类Article
英文摘要Phosphoglycerate mutase 1 (PGAM1), an important enzyme in glycolysis, is overexpressed in a number of human cancers, thus has been proposed as a promising metabolic target for cancer treatments. The C-terminal portion of the available crystal structures of PGAM1 and its homologous proteins is partially disordered, as evidenced by weak electron density. In this study, we identified the conformational behavior of the C-terminal region of PGAM1 as well as its role during the catalytic cycle. Using the PONDR-FIT server, we demonstrated that the C-terminal region was intrinsically disordered. We applied the Monte Carlo (MC) method to explore the conformational space of the C-terminus and conducted a series of explicit-solvent molecular dynamics (MD) simulations, and revealed that the C-terminal region is inherently dynamic; large-scale conformational changes in the C-terminal segment led to the structural transition of PGAM1 from the closed state to the open state. Furthermore, the C-terminal segment influenced 2,3-bisphosphoglycerate (2,3-BPG) binding. The proposed swing model illustrated a critical role of the C-terminus in the catalytic cycle through the conformational changes. In conclusion, the C-terminal region induces large movements of PGAM1 from the closed state to the open state and influences cofactor binding during the catalytic cycle. This report describes the dynamic features of the C-terminal region in detail and should aid in design of novel and efficient inhibitors of PGAM1. A swing mechanism of the C-terminal region is proposed, to facilitate further studies of the catalytic mechanism and the physiological functions of its homologues.
WOS关键词HUMAN BISPHOSPHOGLYCERATE MUTASE ; MOLECULAR-DYNAMICS ; CRYSTAL-STRUCTURE ; MECHANICAL CALCULATIONS ; FORCE-FIELD ; SIMULATIONS ; CANCER ; SUBSTRATE ; PHOSPHORYLATION ; IDENTIFICATION
资助项目Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[21472026] ; State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505] ; Shanghai Municipal Committee of Science and Technology[14XD1400300] ; program for Shanghai Rising Star[15QA1400300] ; Computer Network Information Centre, Chinese Academy of Sciences[00000000] ; Guangdong Supercomputing Centre[nsfc2015-446]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:6136216
出版者ACTA PHARMACOLOGICA SINICA
WOS记录号WOS:000416938000009
源URL[http://119.78.100.183/handle/2S10ELR8/272370]  
专题药物发现与设计中心
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Zhou, Lu; Luo, Cheng
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
3.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Liu, Shi-en,Hu, Jun-chi,Zhang, Hao,et al. Conformation and dynamics of the C-terminal region in human phosphoglycerate mutase 1[J]. ACTA PHARMACOLOGICA SINICA,2017,38(12):1673-1682.
APA Liu, Shi-en.,Hu, Jun-chi.,Zhang, Hao.,Xu, Pan.,Wan, Wei.,...&Luo, Cheng.(2017).Conformation and dynamics of the C-terminal region in human phosphoglycerate mutase 1.ACTA PHARMACOLOGICA SINICA,38(12),1673-1682.
MLA Liu, Shi-en,et al."Conformation and dynamics of the C-terminal region in human phosphoglycerate mutase 1".ACTA PHARMACOLOGICA SINICA 38.12(2017):1673-1682.

入库方式： OAI收割

来源：上海药物研究所

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