1hy7

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{{STRUCTURE_1hy7| PDB=1hy7 | SCENE= }}
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==A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3==
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===A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3===
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<StructureSection load='1hy7' size='340' side='right' caption='[[1hy7]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
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{{ABSTRACT_PUBMED_11297453}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1hy7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HY7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1HY7 FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MBS:R-2-{[4-METHOXY-(1,1-BIPHENYL)-4-YL]-SULFONYL}-AMINO-6-METHOXY-HEX-4-YNOIC+ACID'>MBS</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1g49|1g49]], [[1cqr|1cqr]], [[1d5j|1d5j]], [[1d7x|1d7x]], [[1d8f|1d8f]], [[1d8m|1d8m]]</td></tr>
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<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MMP3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Stromelysin_1 Stromelysin 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.17 3.4.24.17] </span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1hy7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hy7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1hy7 RCSB], [http://www.ebi.ac.uk/pdbsum/1hy7 PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/MMP3_HUMAN MMP3_HUMAN]] Defects in MMP3 are the cause of susceptibility to coronary heart disease type 6 (CHDS6) [MIM:[http://omim.org/entry/614466 614466]]. A multifactorial disease characterized by an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. Decreased capacity of the coronary vessels is often associated with thickening and loss of elasticity of the coronary arteries. Note=A polymorphism in the MMP3 promoter region is associated with the risk of coronary heart disease and myocardial infarction, due to lower MMP3 proteolytic activity and higher extracellular matrix deposition in atherosclerotic lesions.<ref>PMID:8662692</ref> <ref>PMID:12477941</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/MMP3_HUMAN MMP3_HUMAN]] Can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates procollagenase.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hy/1hy7_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A series of carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A (MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a compound with reasonable potency. Introduction of polar groups was required in order to generate inhibitors with acceptable water solubility, and this often resulted in a loss of potency as in compound 63. High serum protein binding proved to be a difficult hurdle with many compounds such as 48 showing &gt;99% binding. Some compounds such as 64 displayed approximately 90% binding, but no reliable method was discovered for designing molecules with low protein binding. Finally, selected data regarding the pharmacokinetic behavior of these compounds is presented.
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==Disease==
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Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.,Natchus MG, Bookland RG, Laufersweiler MJ, Pikul S, Almstead NG, De B, Janusz MJ, Hsieh LC, Gu F, Pokross ME, Patel VS, Garver SM, Peng SX, Branch TM, King SL, Baker TR, Foltz DJ, Mieling GE J Med Chem. 2001 Mar 29;44(7):1060-71. PMID:11297453<ref>PMID:11297453</ref>
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[[http://www.uniprot.org/uniprot/MMP3_HUMAN MMP3_HUMAN]] Defects in MMP3 are the cause of susceptibility to coronary heart disease type 6 (CHDS6) [MIM:[http://omim.org/entry/614466 614466]]. A multifactorial disease characterized by an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. Decreased capacity of the coronary vessels is often associated with thickening and loss of elasticity of the coronary arteries. Note=A polymorphism in the MMP3 promoter region is associated with the risk of coronary heart disease and myocardial infarction, due to lower MMP3 proteolytic activity and higher extracellular matrix deposition in atherosclerotic lesions.<ref>PMID:8662692</ref><ref>PMID:12477941</ref>
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[http://www.uniprot.org/uniprot/MMP3_HUMAN MMP3_HUMAN]] Can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates procollagenase.
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</div>
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==About this Structure==
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[[1hy7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HY7 OCA].
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==See Also==
==See Also==
*[[Matrix metalloproteinase|Matrix metalloproteinase]]
*[[Matrix metalloproteinase|Matrix metalloproteinase]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:011297453</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Stromelysin 1]]
[[Category: Stromelysin 1]]

Revision as of 15:49, 29 September 2014

A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3

1hy7, resolution 1.50Å

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