1cqr

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[[Image:1cqr.jpg|left|200px]]<br /><applet load="1cqr" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1cqr, resolution 2.0&Aring;" />
 
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'''CRYSTAL STRUCTURE OF THE STROMELYSIN CATALYTIC DOMAIN AT 2.0 A RESOLUTION'''<br />
 
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==Overview==
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==CRYSTAL STRUCTURE OF THE STROMELYSIN CATALYTIC DOMAIN AT 2.0 A RESOLUTION==
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Matrix metalloproteinases are believed to play an important role in pathological conditions such as osteoarthritis, rheumatoid arthritis and tumor invasion. Stromelysin is a zinc-dependent proteinase and a member of the matrix metalloproteinase family. We have solved the crystal structure of an active uninhibited form of truncated stromelysin and a complex with a hydroxamate-based inhibitor. The catalytic domain of the enzyme of residues 83-255 is an active fragment. Two crystallographically independent molecules, A and B, associate as a dimer in the crystals. There are three alpha-helices and one twisted, five-strand beta-sheet in each molecule, as well as one catalytic Zn, one structural Zn and three structural Ca ions. The active site of stromelysin is located in a large, hydrophobic cleft. In particular, the S1' specificity site is a deep and highly hydrophobic cavity. The structure of a hydroxamate-phosphinamide-type inhibitor-bound stromelysin complex, formed by diffusion soaking, has been solved as part of our structure-based design strategy. The most important feature we observed is an inhibitor-induced conformational change in the S1' cavity which is triggered by Tyr223. In the uninhibited enzyme structure, Tyr223 completely covers the S1' cavity, while in the complex, the P1' group of the inhibitor displaces the Tyr223 in order to fit into the S1' cavity. Furthermore, the displacement of Tyr223 induces a major conformational change of the entire loop from residue 222 to residue 231. This finding provides direct evidence that Tyr223 plays the role of gatekeeper of the S1' cavity. Another important intermolecular interaction occurs at the active sit of molecule A, in which the C-terminal tail (residues 251-255) from molecule B inserts. The C-terminal tail interacts extensively with the active site of molecule A, and the last residue (Thr255) coordinated to the catalytic zinc as the fourth ligand, much like a product inhibitor would. The inhibitor-induced conformational change and the intermolecular C-terminal-zinc coordination are significant in understanding the structure-activity relationships of the enzyme.
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<StructureSection load='1cqr' size='340' side='right'caption='[[1cqr]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1cqr]] 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=1CQR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1CQR 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&#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=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=1cqr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1cqr OCA], [https://pdbe.org/1cqr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1cqr RCSB], [https://www.ebi.ac.uk/pdbsum/1cqr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1cqr 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/cq/1cqr_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=1cqr 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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1CQR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=CA:'>CA</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=1CQR OCA].
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__TOC__
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</StructureSection>
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==Reference==
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Crystal structure of the stromelysin catalytic domain at 2.0 A resolution: inhibitor-induced conformational changes., Chen L, Rydel TJ, Gu F, Dunaway CM, Pikul S, Dunham KM, Barnett BL, J Mol Biol. 1999 Oct 29;293(3):545-57. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10543949 10543949]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Stromelysin 1]]
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[[Category: Barnett BL]]
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[[Category: Barnett, B L.]]
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[[Category: Chen L]]
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[[Category: Chen, L.]]
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[[Category: Dunaway CM]]
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[[Category: Dunaway, C M.]]
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[[Category: Dunham KM]]
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[[Category: Dunham, K M.]]
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[[Category: Gu F]]
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[[Category: Gu, F.]]
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[[Category: Pikul S]]
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[[Category: Pikul, S.]]
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[[Category: Rydel TJ]]
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[[Category: Rydel, T J.]]
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[[Category: CA]]
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[[Category: ZN]]
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[[Category: active]]
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[[Category: truncated native enzyme]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:08:46 2008''
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Current revision

CRYSTAL STRUCTURE OF THE STROMELYSIN CATALYTIC DOMAIN AT 2.0 A RESOLUTION

PDB ID 1cqr

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