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Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase

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An Erratum to this article was published on 07 October 2014

Abstract

Human monoacylglycerol lipase (MGL) catalyzes the hydrolysis of 2-arachidonoylglycerol to arachidonic and glycerol, which plays a pivotal role in the normal biological processes of brain. Co-crystal structure of the MGL in complex with its inhibitor, compound 1, shows that the helix α4 undergoes large-scale conformational changes in response to the compound 1 binding compared to the apo MGL. However, the detailed conformational transition pathway of the helix α4 in the inhibitor binding process of MGL has remained unclear. Here, conventional molecular dynamics (MD) and nudged elastic band (NEB) simulations were performed to explore the conformational transition pathway of the helix α4. Conventional MD simulations unveiled that the compound 1 induced the closed conformation of the active site of MGL, reduced the conformational flexibility of the helix α4, and elicited the large-scale conformational rearrangement of the helix α4, leading to the complete folding of the helix α4. Moreover, NEB simulations revealed that the conformational transition pathway of helix α4 underwent an almost 180° counter-clockwise rotation of the helix α4. Our computational results advance the structural and mechanistic understanding of the inhibitory mechanism.

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Abbreviations

2-AG:

2-Arachidonoylglycerol

CNS:

Central nervous system

DCCM:

Dynamical cross-correlation matrices

DSSP:

Defined secondary structure of proteins

MD:

Molecular dynamics

MGL:

Monoacylglycerol lipase

NEB:

Nudged elastic band

RMSD:

Root-mean-square deviation

RMSF:

Root-mean-square fluctuation

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Acknowledgments

This study was supported by the National Key Basic Research Program of China (973 Program, No. 2011CBA00800), the Open Funding Project of National Key Laboratory of Biochemical Engineering, and the Key Agriculture Support Project of Jiangsu Province (No. BE2013400).

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Authors and Affiliations

  1. Institute of Life Sciences, Jiangsu University, Zhenjiang, 212013, China

    Huayou Chen, Rui Tian, Zhong Ni & Qi Guo

  2. Division of Biological Sciences, University of California at San Diego, La Jolla, CA, 92093-0116, USA

    Huayou Chen, Zhongge Zhang & Milton H. Saier Jr.

  3. National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 10090, China

    Huayou Chen & Hongzhang Chen

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  1. Huayou Chen
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Correspondence to Milton H. Saier Jr..

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Chen, H., Tian, R., Ni, Z. et al. Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase. Protein J 33, 503–511 (2014). https://doi.org/10.1007/s10930-014-9572-z

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