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

Crystal structure of the human monoacylglycerol lipase, a key actor in
endocannabinoid signaling.

Labar G, Bauvois C, Borel F, Ferrer JL, Wouters J, Lambert DM.

Unité de Chimie Pharmaceutique et de Radiopharmacie (CMFA), Louvain Drug Research
Institute, Université catholique de Louvain, Faculté de Médecine, Avenue E.
Mounier 73.40, 1200 Brussels, Belgium.

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.

PMID: 19957260 [PubMed - indexed for MEDLINE]