1hfs: Difference between revisions

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-[[Image:1hfs.gif|left|200px]]<br />
-<applet load="1hfs" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1hfs, resolution 1.70&Aring;" />
-'''CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THE N-CARBOXY-ALKYL INHIBITOR L-764,004'''<br />
-==Overview==
+==CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THE N-CARBOXY-ALKYL INHIBITOR L-764,004==
-Carboxyalkyl peptides containing a biphenylylethyl group at the P1', position were found to be potent inhibitors of stromelysin-1 (MMP-3) and, gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of, collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a, tert-butyl group at P2', and a methyl group at P3' produced orally, bioavailable inhibitors as measured by an in vivo model of MMP-3, degradation of radiolabeled transferrin in the mouse pleural cavity. The, X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic, domain of MMP-3 is described. Inhibitors that contained halogenated, biphenylylethyl residues at P1' proved to be superior in terms of enzyme, potency and oral activity with, 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid, 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a, Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural, cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta, injection in the rabbit) and chronic (rat adjuvant-induced arthritis and, mouse collagen-induced arthritis) models of cartilage destruction but, showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).
+<StructureSection load='1hfs' size='340' side='right'caption='[[1hfs]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1hfs]] 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=1HFS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1HFS 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]] 1.7&#8491;</td></tr>
+<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=L04:6-(4-FLUORO-BIPHENYL-4-YL)-4-(3-METHYL-1-PHENYLCARBAMOYL-BUTYLCARBAMOYL)-2-[4-(1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-BUTYL]-HEXANOIC+ACID'>L04</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=1hfs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hfs OCA], [https://pdbe.org/1hfs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1hfs RCSB], [https://www.ebi.ac.uk/pdbsum/1hfs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1hfs ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[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>
+== Function ==
+[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.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hf/1hfs_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</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=1hfs ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-HFS 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 ZN, CA and L04 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] Structure known Active Sites: CA1, CA2, CA3, L04, ZN1 and ZN2. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1HFS OCA].
+*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
+== References ==
-==Reference==
+<references/>
-Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides., Esser CK, Bugianesi RL, Caldwell CG, Chapman KT, Durette PL, Girotra NN, Kopka IE, Lanza TJ, Levorse DA, MacCoss M, Owens KA, Ponpipom MM, Simeone JP, Harrison RK, Niedzwiecki L, Becker JW, Marcy AI, Axel MG, Christen AJ, McDonnell J, Moore VL, Olszewski JM, Saphos C, Visco DM, Hagmann WK, et al., J Med Chem. 1997 Mar 14;40(6):1026-40. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9083493 9083493]
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Stromelysin 1]]
+[[Category: Becker JW]]
-[[Category: Becker, J.W.]]
-[[Category: CA]]
-[[Category: L04]]
-[[Category: ZN]]
-[[Category: hydrolase]]
-[[Category: matrix metalloprotease-3]]
-[[Category: metalloprotease]]
-[[Category: proteoglycanase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov  5 15:00:12 2007''