ICCAS OpenIR
Microsomal prostaglandin E synthase-1 exhibits one-third-of-the-sites reactivity
He, Shan1; Wu, Yiran1; Yu, Daqi1; Lai, Luhua1,2
2011-11-15
Source PublicationBIOCHEMICAL JOURNAL
ISSN0264-6021
Volume440Pages:13-21
AbstractmPGES-1 (microsomal prostaglandin E synthase-1) is a newly recognized target for the treatment of inflammatory diseases. As the terminal enzyme of the prostaglandin production pathway, mPGES-1 inhibition may have a low risk of side effects. Inhibitors of mPGES-1 have attracted considerable attention as next-generation anti-inflammatory drugs. However, as mPGES-1 is a membrane protein, its enzymatic mechanism remains to be disclosed fully. We used MD (molecular dynamics) simulations, mutation analysis, hybrid experiments and co-IP (co-immunoprecipitation) to investigate the conformation transitions of mPGES-1 during catalysis. mPGES-1 forms a homotrimer with three substrate-binding sites (pockets). In the MD simulation, only one substrate molecule could bind to one of the pockets and form the active complex, suggesting that the mPGES-1 trimer has only one pocket active at any given time. This one-third-of-the-sites reactivity enzyme mechanism was verified further by hybridization experiments and MD simulations. The results of the present study revealed for the first time a novel one-third-of-the-sites reactivity enzyme mechanism for mPGES-1, and the unique substrate-binding pocket in our model constituted an active conformation that was suitable for further enzymatic mechanism study and structural-based drug design against mPGES-1.
KeywordDrug Design Enzyme Mechanism Inflammation Membrane-associated ProteIns In Eicosanoid And Glutathione Metabolism (Mapeg) Microsomal Prostaglandin e Synthase-1 (Mpges-1) One-third-of-the-sites Reactivity
DOI10.1042/BJ20110977
Indexed BySCI
Language英语
WOS IDWOS:000297233900002
PublisherPORTLAND PRESS LTD
Citation statistics
Document Type期刊论文
Identifierhttp://ir.iccas.ac.cn/handle/121111/72756
Collection中国科学院化学研究所
Corresponding AuthorLai, Luhua
Affiliation1.Peking Univ, Beijing Natl Lab Mol Sci, State Key Lab Struct Chem Unstable & Stable Speci, Coll Chem & Mol Engn, Beijing 100871, Peoples R China
2.Peking Univ, Ctr Theoret Biol, AAIS, Beijing 100871, Peoples R China
Recommended Citation
GB/T 7714
He, Shan,Wu, Yiran,Yu, Daqi,et al. Microsomal prostaglandin E synthase-1 exhibits one-third-of-the-sites reactivity[J]. BIOCHEMICAL JOURNAL,2011,440:13-21.
APA He, Shan,Wu, Yiran,Yu, Daqi,&Lai, Luhua.(2011).Microsomal prostaglandin E synthase-1 exhibits one-third-of-the-sites reactivity.BIOCHEMICAL JOURNAL,440,13-21.
MLA He, Shan,et al."Microsomal prostaglandin E synthase-1 exhibits one-third-of-the-sites reactivity".BIOCHEMICAL JOURNAL 440(2011):13-21.
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