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

Geoffray Labar, Cédric Bauvois, Franck Borel, Jean L. Ferrer, Johan Wouters, Didier M. Lambert

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)218-227
Number of pages10
Issue number2
Publication statusPublished - 25 Jan 2010


  • Crystal structures
  • Enzymes
  • Inhibitors
  • Monoacylglycerol lipase
  • Monoglyceride lipase
  • N-arachidoyl maleimide


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