mPGES-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.
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Research Article|
October 27 2011
Microsomal prostaglandin E synthase-1 exhibits one-third-of-the-sites reactivity
Shan He;
Shan He
*Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
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Yiran Wu;
Yiran Wu
*Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
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Daqi Yu;
Daqi Yu
*Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
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Luhua Lai
Luhua Lai
1
*Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
†Center for Theoretical Biology, AAIS, Peking University, Beijing 100871, China
1To whom correspondence should be addressed (email lhlai@pku.edu.cn).
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Publisher: Portland Press Ltd
Received:
June 01 2011
Revision Received:
July 29 2011
Accepted:
July 29 2011
Accepted Manuscript online:
July 29 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 440 (1): 13–21.
Article history
Received:
June 01 2011
Revision Received:
July 29 2011
Accepted:
July 29 2011
Accepted Manuscript online:
July 29 2011
Citation
Shan He, Yiran Wu, Daqi Yu, Luhua Lai; Microsomal prostaglandin E synthase-1 exhibits one-third-of-the-sites reactivity. Biochem J 15 November 2011; 440 (1): 13–21. doi: https://doi.org/10.1042/BJ20110977
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