Structural Basis for Human Monoglyceride Lipase Inhibition
Structural Basis for Human Monoglyceride Lipase Inhibition
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DOI：
10.1016/j.jmb.2009.11.060
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发表时间：
2010-02-26
影响因子：
5.6
通讯作者：
Mathieu, M.
中科院分区：
文献类型：
--
作者：
Bertrand, T.;Auge, F.;Mathieu, M.
甘油单酯脂肪酶（MGL）是一种丝氨酸水解酶，可将2-花生四烯酸甘油（2-AG）水解为花生四烯酸和甘油。2-AG是大麻素受体的内源性配体，参与大脑中的各种生理过程。我们在这里提出的第一个晶体结构的人MGL在其载脂蛋白的形式，并与共价抑制剂SAR 629的复合物。MGL与α/β水解酶家族共享经典折叠，但描绘了异常大的疏水封闭隧道，在其入口处具有高度柔性的盖子，并且催化三联体埋在其末端。结构揭示了催化三联体的构型以及2-AG结合位点的形状和性质。SAR 629的结合结构突出了与MGL有效结合的关键相互作用。隧道的形状表明蛋白质的高度可药性，并为药物发现提供了有吸引力的模板。(C)2009爱思唯尔有限公司保留所有权利。
Monoglyceride lipase (MGL) is a serine hydrolase that hydrolyses 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. 2-AG is an endogenous ligand of cannabinoid receptors, involved in various physiological processes in the brain. We present here the first crystal structure of human MGL in its apo form and in complex with the covalent inhibitor SAR629. MGL shares the classic fold of the alpha/beta hydrolase family but depicts an unusually large hydrophobic occluded tunnel with a highly flexible lid at its entry and the catalytic triad buried at its end. Structures reveal the configuration of the catalytic triad and the shape and nature of the binding site of 2-AG. The bound structure of SAR629 highlights the key interactions for productive binding with MGL. The shape of the tunnel suggests a high druggability of the protein and provides an attractive template for drug discovery. (C) 2009 Elsevier Ltd. All rights reserved.