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.
Chembiochem. 2010 Jan 25;11(2):218-27. doi: 10.1002/cbic.200900621.
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.
2-花生四烯酸甘油在内源性大麻素信号中起着重要作用，其受到单酰基甘油脂肪酶（MAGL）的严格调控。本文报道了人源 MAGL 的晶体结构。该蛋白以二聚体形式结晶，尽管与过氧化物酶和酯酶具有结构同源性，但它通过广泛的疏水性进入催化位点而与众不同。覆盖活性位点的非极性螺旋也为 MAGL 的两亲性特征提供了结构上的见解，并可能解释了 MAGL 如何与膜相互作用以募集其底物。2-花生四烯酸甘油的对接突出了一个疏水性和亲水性腔，可将脂质容纳在催化位点中。此外，我们确定半胱氨酸 201 是 N-花生四烯酰马来酰亚胺抑制 MAGL 的关键残基，N-花生四烯酰马来酰亚胺是一种巯基反应性化合物。除了对内源性大麻素降解途径的认识有所提高外，MAGL 的结构还为未来旨在利用 2-花生四烯酸甘油传递设计新药的药物化学工作铺平了道路。
