1a85

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[[Image:1a85.gif|left|200px]]<br /><applet load="1a85" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1a85, resolution 2.0&Aring;" />
 
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'''MMP8 WITH MALONIC AND ASPARAGINE BASED INHIBITOR'''<br />
 
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==Overview==
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==MMP8 WITH MALONIC AND ASPARAGINE BASED INHIBITOR==
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Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures.
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<StructureSection load='1a85' size='340' side='right'caption='[[1a85]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1a85]] 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=1A85 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1A85 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=0DY:N~1~-(3-AMINOBENZYL)-N~2~-[(2R)-2-(HYDROXYCARBAMOYL)-4-METHYLPENTANOYL]-L-ASPARTAMIDE'>0DY</scene>, <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=1a85 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1a85 OCA], [https://pdbe.org/1a85 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1a85 RCSB], [https://www.ebi.ac.uk/pdbsum/1a85 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1a85 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/MMP8_HUMAN MMP8_HUMAN] Can degrade fibrillar type I, II, and III collagens.
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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/a8/1a85_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=1a85 ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1A85 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=CA:'>CA</scene>, <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=HMI:'>HMI</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Neutrophil_collagenase Neutrophil collagenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.34 3.4.24.34] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1A85 OCA].
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*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data., Brandstetter H, Engh RA, Von Roedern EG, Moroder L, Huber R, Bode W, Grams F, Protein Sci. 1998 Jun;7(6):1303-9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9655333 9655333]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Neutrophil collagenase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Brandstetter H]]
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[[Category: Brandstetter, H.]]
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[[Category: Engh RA]]
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[[Category: Engh, R A.]]
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[[Category: Grams F]]
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[[Category: Grams, F.]]
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[[Category: Roedern EGV]]
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[[Category: Roedern, E G.V.]]
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[[Category: CA]]
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[[Category: HMI]]
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[[Category: ZN]]
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[[Category: collagenase]]
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[[Category: complex (collagenase/inhibitor)]]
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[[Category: malonic acid]]
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[[Category: matrix metalloproteinase]]
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[[Category: mmp8]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:41:59 2008''
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Current revision

MMP8 WITH MALONIC AND ASPARAGINE BASED INHIBITOR

PDB ID 1a85

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