1d5j

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[[Image:1d5j.gif|left|200px]]<br /><applet load="1d5j" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1d5j, resolution 2.6&Aring;" />
 
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'''CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.'''<br />
 
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==Overview==
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==CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.==
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The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.
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<StructureSection load='1d5j' size='340' side='right'caption='[[1d5j]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1d5j]] 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=1D5J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1D5J FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MM3:N-HYDROXY-4-[(4-METHOXYLPHENYL)SULFONYL]-2,2-DIMETHYL-HEXAHYDRO-1,4-THIAZEPINE-3(S)-CARBOXAMIDE'>MM3</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1d5j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1d5j OCA], [https://pdbe.org/1d5j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1d5j RCSB], [https://www.ebi.ac.uk/pdbsum/1d5j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1d5j ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/MMP3_HUMAN MMP3_HUMAN] Defects in MMP3 are the cause of susceptibility to coronary heart disease type 6 (CHDS6) [MIM:[https://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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[https://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/d5/1d5j_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/main_output.php?pdb_ID=1d5j ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known diseases associated with this structure: Coronary heart disease, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=185250 185250]]
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*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1D5J is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=MM3:'>MM3</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D5J OCA].
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__TOC__
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</StructureSection>
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==Reference==
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[[Category: Homo sapiens]]
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Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors., Almstead NG, Bradley RS, Pikul S, De B, Natchus MG, Taiwo YO, Gu F, Williams LE, Hynd BA, Janusz MJ, Dunaway CM, Mieling GE, J Med Chem. 1999 Nov 4;42(22):4547-62. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10579818 10579818]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Almstead NG]]
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[[Category: Stromelysin 1]]
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[[Category: Bradley RS]]
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[[Category: Almstead, N G.]]
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[[Category: De B]]
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[[Category: Bradley, R S.]]
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[[Category: Natchus MG]]
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[[Category: De, B.]]
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[[Category: Pikul S]]
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[[Category: Natchus, M G.]]
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[[Category: Pikul, S.]]
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[[Category: CA]]
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[[Category: MM3]]
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[[Category: ZN]]
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[[Category: inhibited]]
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[[Category: mixed alpha beta structure]]
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[[Category: zinc protease]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:13:11 2008''
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Current revision

CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.

PDB ID 1d5j

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