6bq0
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Structure of human monoacylglycerol lipase bound to a covalent inhibitor== | |
| + | <StructureSection load='6bq0' size='340' side='right' caption='[[6bq0]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6bq0]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BQ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BQ0 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E3A:1-({(1R,5S,6r)-6-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carbonyl}oxy)pyrrolidine-2,5-dione'>E3A</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acylglycerol_lipase Acylglycerol lipase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.23 3.1.1.23] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bq0 OCA], [http://pdbe.org/6bq0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bq0 RCSB], [http://www.ebi.ac.uk/pdbsum/6bq0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bq0 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/MGLL_HUMAN 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.<ref>PMID:20079333</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway, and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group which confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure; while simultaneously, reducing LogD, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge. | ||
| - | + | Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation.,McAllister LA, Butler CR, Mente S, O'Neil SV, Fonseca KR, Piro JR, Cianfrogna JA, Foley TL, Gilbert AM, Harris AR, Helal CJ, Johnson DS, Montgomery JI, Nason DM, Noell S, Pandit J, Rogers BN, Samad TA, Shaffer CL, da Silva RG, Uccello DP, Webb D, Brodney MA J Med Chem. 2018 Mar 2. doi: 10.1021/acs.jmedchem.8b00070. PMID:29498843<ref>PMID:29498843</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6bq0" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Acylglycerol lipase]] | ||
[[Category: Pandit, J]] | [[Category: Pandit, J]] | ||
| + | [[Category: Covalent inhibitor]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
| + | [[Category: Monoacylglycerol lipase]] | ||
| + | [[Category: Sbdd]] | ||
Revision as of 06:30, 14 March 2018
Structure of human monoacylglycerol lipase bound to a covalent inhibitor
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