View source for 8ptc


==COMPLEX CRYSTAL STRUCTURE OF MUTANT HUMAN MONOGLYCERIDE LIPASE WITH COMPOUND 5d==
<StructureSection load='8ptc' size='340' side='right'caption='[[8ptc]], [[Resolution|resolution]] 1.51&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ptc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8PTC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PTC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.51&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=F28:4-[(3~{R},4~{S})-2-oxidanylidene-3,4-diphenyl-azetidin-1-yl]piperidine-1-carbaldehyde'>F28</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8ptc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ptc OCA], [https://pdbe.org/8ptc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ptc RCSB], [https://www.ebi.ac.uk/pdbsum/8ptc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ptc ProSAT]</span></td></tr>
</table>
== Function ==
[https://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 ==
New potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((+/-)-5a-v, (+/-)-6a-j, and (+/-)-7a-d) were developed as irreversible ligands, as demonstrated by enzymatic and crystallographic studies for (+/-)-5d, (+/-)-5l, and (+/-)-5r. X-ray analyses combined with extensive computational studies allowed us to clarify the binding mode of the compounds. 5v was identified as selective for MAGL when compared with other serine hydrolases. Solubility, in vitro metabolic stability, cytotoxicity, and absence of mutagenicity were determined for selected analogues. The most promising compounds ((+/-)-5c, (+/-)-5d, and (+/-)-5v) were used for in vivo studies in mice, showing a decrease in MAGL activity and increased 2-arachidonoyl-sn-glycerol levels in forebrain tissue. In particular, 5v is characterized by a high eudysmic ratio and (3R,4S)-5v is one of the most potent irreversible inhibitors of h/mMAGL identified thus far. These results suggest that the new MAGL inhibitors have therapeutic potential for different central and peripheral pathologies.

Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization.,Butini S, Grether U, Jung KM, Ligresti A, Allara M, Postmus AGJ, Maramai S, Brogi S, Papa A, Carullo G, Sykes D, Veprintsev D, Federico S, Grillo A, Di Guglielmo B, Ramunno A, Stevens AF, Heer D, Lamponi S, Gemma S, Benz J, Di Marzo V, van der Stelt M, Piomelli D, Campiani G J Med Chem. 2024 Feb 8;67(3):1758-1782. doi: 10.1021/acs.jmedchem.3c01278. Epub , 2024 Jan 19. PMID:38241614<ref>PMID:38241614</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ptc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Benz J]]
[[Category: Butini S]]
[[Category: Campiani G]]
[[Category: Carullo G]]
[[Category: Di Guglielmo B]]
[[Category: Federico S]]
[[Category: Gemma S]]
[[Category: Grether U]]
[[Category: Grillo A]]
[[Category: Lamponi S]]
[[Category: Leibrock L]]
[[Category: Maramai S]]
[[Category: Papa A]]