期刊
CHEMISTRY & BIOLOGY
卷 16, 期 10, 页码 1045-1052出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2009.09.012
关键词
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资金
- National Institute on Drug Abuse [R01 DA-012447]
- NIH [T32NS007444-7]
- Italian Ministry of University and Research [2005032713_002]
Monoacylglycerol lipase (MGL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Prep vious efforts to design MGL inhibitors have focused on chemical scaffolds that irreversibly block the activity of this enzyme. Here, we describe two naturally occurring terpenoids, pristimerin and euphol, which inhibit MGL activity with high potency (median effective concentration, IC50 = 93 nM and 315 nM, respectively) through a reversible mechanism. Mutational and modeling studies suggest that the two agents occupy a common hydrophobic pocket located within the putative lid domain of MGL, and each reversibly interacts with one of two adjacent cysteine residues (Cys(201) and Cys(208)) flanking such pocket. This previously unrecognized regulatory region might offer a molecular target for potent and reversible inhibitors of MGL.
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