7ZPG

CRYSTAL STRUCTURE OF HUMAN MONOGLYCERIDE LIPASE WITH LIGAND

7ZPG の概要

• エントリーDOI: 10.2210/pdb7zpg/pdb
• 分子名称: Monoglyceride lipase, [(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromanyl-3-methoxy-phenyl)methanone (3 entities in total)
• 機能のキーワード: alpha/beta hydrolase, hydrolase, serine esterase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35929.31

構造登録者

Kemble, A.,Hornsperger, B.,Ruf, I.,Richter, H.,Benz, J.,Kuhn, B.,Heer, D.,Wittwer, M.,Engelhardt, B.,Grether, U.,Collin, L.,Leibrock, L. (登録日: 2022-04-27, 公開日: 2022-09-21, 最終更新日: 2024-05-01)

主引用文献

Kemble, A.M.,Hornsperger, B.,Ruf, I.,Richter, H.,Benz, J.,Kuhn, B.,Heer, D.,Wittwer, M.,Engelhardt, B.,Grether, U.,Collin, L.
A potent and selective inhibitor for the modulation of MAGL activity in the neurovasculature.
Plos One, 17:e0268590-e0268590, 2022

PubMed Abstract: Chronic inflammation and blood-brain barrier dysfunction are key pathological hallmarks of neurological disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. Major drivers of these pathologies include pro-inflammatory stimuli such as prostaglandins, which are produced in the central nervous system by the oxidation of arachidonic acid in a reaction catalyzed by the cyclooxygenases COX1 and COX2. Monoacylglycerol lipase hydrolyzes the endocannabinoid signaling lipid 2-arachidonyl glycerol, enhancing local pools of arachidonic acid in the brain and leading to cyclooxygenase-mediated prostaglandin production and neuroinflammation. Monoacylglycerol lipase inhibitors were recently shown to act as effective anti-inflammatory modulators, increasing 2-arachidonyl glycerol levels while reducing levels of arachidonic acid and prostaglandins, including PGE2 and PGD2. In this study, we characterized a novel, highly selective, potent and reversible monoacylglycerol lipase inhibitor (MAGLi 432) in a mouse model of lipopolysaccharide-induced blood-brain barrier permeability and in both human and mouse cells of the neurovascular unit: brain microvascular endothelial cells, pericytes and astrocytes. We confirmed the expression of monoacylglycerol lipase in specific neurovascular unit cells in vitro, with pericytes showing the highest expression level and activity. However, MAGLi 432 did not ameliorate lipopolysaccharide-induced blood-brain barrier permeability in vivo or reduce the production of pro-inflammatory cytokines in the brain. Our data confirm monoacylglycerol lipase expression in mouse and human cells of the neurovascular unit and provide the basis for further cell-specific analysis of MAGLi 432 in the context of blood-brain barrier dysfunction caused by inflammatory insults.

PubMed: 36084029
DOI: 10.1371/journal.pone.0268590

実験手法

X-RAY DIFFRACTION (1.16 Å)