Crystal structure of the human monoacylglycerol lipase, a key actor in endocannabinoid signaling.
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.
Labar
Geoffray
G
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.
Bauvois
Cédric
C
Borel
Franck
F
Ferrer
Jean-Luc
JL
Wouters
Johan
J
Lambert
Didier M
DM
D001095:Arachidonic Acids / Q000737:chemistry; D001665:Binding Sites; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D063388:Endocannabinoids; D005989:Glycerides / Q000737:chemistry; D006801:Humans; D008301:Maleimides / Q000737:chemistry / Q000494:pharmacology; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction; D013379:Substrate Specificity
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D008301:Maleimides; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases