8aqf | pdb_00008aqf

CRYSTAL STRUCTURE OF HUMAN MONOGLYCERIDE LIPASE WITH COMPOUND LEI-515

spinqualitylabelsall models 8aqf, resolution 1.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8aqf is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.55Å Ligands: NUX Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MGLL_HUMAN Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (By similarity). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth. Publication Abstract from PubMed Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl(4)-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB(1) activation. Antinociceptive efficacy of LEI-515 was blocked by CB(2), but not CB(1), antagonists. The CB(1) antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents. A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence.,Jiang M, Huizenga MCW, Wirt JL, Paloczi J, Amedi A, van den Berg RJBHN, Benz J, Collin L, Deng H, Di X, Driever WF, Florea BI, Grether U, Janssen APA, Hankemeier T, Heitman LH, Lam TW, Mohr F, Pavlovic A, Ruf I, van den Hurk H, Stevens AF, van der Vliet D, van der Wel T, Wittwer MB, van Boeckel CAA, Pacher P, Hohmann AG, van der Stelt M Nat Commun. 2023 Dec 5;14(1):8039. doi: 10.1038/s41467-023-43606-3. PMID:38052772 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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