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Crystal Structure of the Human Monoacylglycerol Lipase, a Key Actor in Endocannabinoid Signaling.

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Labar, Geoffray [UCL] Bauvois, Cédric Borel, Franck Ferrer, Jean-Luc Wouters, Johan [FUNDP] Lambert, Didier [UCL]

2-Arachidonoylglycerol plays a major role in endocannabinoid signaling, and is tightly regulated by the monoacylglycerol lipase (MAGL). Here we report the crystal structure of human MAGL. The protein crystallizes as a dimer, and despite structural homologies to haloperoxidases and esterases, it distinguishes itself by a wide and hydrophobic access to the catalytic site. An apolar helix covering the active site also gives structural insight into the amphitropic character of MAGL, and likely explains how MAGL interacts with membranes to recruit its substrate. Docking of 2-arachidonoylglycerol highlights a hydrophobic and a hydrophilic cavity that accommodate the lipid into the catalytic site. Moreover, we identified Cys201 as the crucial residue in MAGL inhibition by N-arachidonylmaleimide, a sulfhydryl-reactive compound. Beside the advance in the knowledge of endocannabinoids degradation routes, the structure of MAGL paves the way for future medicinal chemistry works aimed at the design of new drugs exploiting 2-arachidonoylglycerol transmission.

Document type Article de périodique (Journal article) – Article de recherche – Journal Article, Research Support, Non-U.S. Gov't
Publication date 2010
Language Anglais
Journal information "ChemBioChem" - Vol. 11, no. 2, p. 218-227 (2010)
Peer reviewed yes
Publisher Wiley - V C H Verlag GmbH & Co. KGaA ((Germany) Weinheim)
issn 1439-4227
e-issn 1439-7633
Publication status Publié
Affiliations UCL - SSS/LDRI - Louvain Drug Research Institute
FUNDP - SCHI_GCPTS (groupe de chimie physique, théorique et structurale)
MESH Subject Substrate Specificity ; Signal Transduction ; Protein Conformation ; Protein Binding ; Monoacylglycerol Lipases - antagonists & inhibitors - chemistry - metabolism ; Maleimides - chemistry - pharmacology ; Humans ; Glycerides - chemistry ; Endocannabinoids - metabolism ; Drug Design ; Computer Simulation ; Catalytic Domain ; Binding Sites ; Arachidonic Acids - chemistry
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Bibliographic reference Labar, Geoffray ; Bauvois, Cédric ; Borel, Franck ; Ferrer, Jean-Luc ; Wouters, Johan ; et. al. Crystal Structure of the Human Monoacylglycerol Lipase, a Key Actor in Endocannabinoid Signaling.. In: ChemBioChem, Vol. 11, no. 2, p. 218-227 (2010)
Permanent URL http://hdl.handle.net/2078.1/28818