8h78: Difference between revisions
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==Crystal structure of human MMP-2 catalytic domain in complex with inhibitor== | |||
<StructureSection load='8h78' size='340' side='right'caption='[[8h78]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8h78]] is a 2 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=8H78 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8H78 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2HP:DIHYDROGENPHOSPHATE+ION'>2HP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=L2U:(2~{R})-2-[[4-[(4-aminocarbonylphenyl)carbonylamino]phenyl]sulfonylamino]-5-[(2~{S},4~{S})-4-azanyl-2-[[(2~{S})-1-[[(2~{S})-1-[(5-azanyl-5-oxidanylidene-pentyl)amino]-5-oxidanyl-1,5-bis(oxidanylidene)pentan-2-yl]-methyl-amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamoyl]pyrrolidin-1-yl]-5-oxidanylidene-pentanoic+acid'>L2U</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8h78 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8h78 OCA], [https://pdbe.org/8h78 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8h78 RCSB], [https://www.ebi.ac.uk/pdbsum/8h78 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8h78 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule-peptide hybrid 1, the tripeptide linker 5-aminopentanoic acid [Ape(5)]-Glu-Asp of 1 was replaced by a shorter linker (gamma-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1' pocket-binding group. The introduction of (4S)-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition (K(i) = 0.034 nM) and >/=2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life (t(1/2) = 265 min). | |||
Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase-2 Inhibitor with a Phenylbenzamide-Pentapeptide Hybrid Scaffold.,Takeuchi T, Nomura Y, Tamita T, Nishikawa R, Kakinuma H, Kojima N, Hitaka K, Tamura Y, Kamitani M, Mima M, Nozoe A, Hayashi M J Med Chem. 2023 Jan 12;66(1):822-836. doi: 10.1021/acs.jmedchem.2c01698. Epub , 2023 Jan 3. PMID:36595440<ref>PMID:36595440</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8h78" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Kamitani M]] | |||
[[Category: Mima M]] | |||
[[Category: Takeuchi T]] | |||
Revision as of 07:34, 18 January 2023
Crystal structure of human MMP-2 catalytic domain in complex with inhibitor
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