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

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

Geoffray Labar, Cédric Bauvois, Franck Borel, Jean-Luc Ferrer, Johan Wouters, Didier M Lambert

Chembiochem. 2010 Jan 25;11(2):218-27.

PMID: 19957260

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP876305429	N-Arachidonylmaleimide		876305-42-9	Price

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