1jh1

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[[Image:1jh1.jpg|left|200px]]<br /><applet load="1jh1" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1jh1, resolution 2.7&Aring;" />
 
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'''Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor'''<br />
 
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==Overview==
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==Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor==
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We describe a new generation of heterocyclic nonpeptide matrix, metalloproteinase (MMP) inhibitors derived from a 6H-1,3,4-thiadiazine, scaffold. A screening effort was utilized to identify some chiral, 6-methyl-1,3,4-thiadiazines that are weak inhibitors of the catalytic, domain of human neutrophil collagenase (cdMMP-8). Further optimization of, the lead compounds revealed general design principles that involve the, placement of a phenyl or thienyl group at position 5 of the thiadiazine, ring, to improve unprimed side affinity; the incorporation of an amino, group at position 2 of the thiadiazine ring as the chelating agent for the, catalytic zinc; the placement of a N-sulfonamide-substituted amino acid, residue at the amino group, to improve primed side affinity; and the, attachment of diverse functional groups at position 4 or 5 of the phenyl, or thienyl group at the unprimed side, to improve selectivity. The new, compounds were assayed against eight different matrix metalloproteinases, MMP-1, cdMMP-2, cdMMP-8, MMP-9, cdMMP-12, cdMMP-13, cdMMP-14, and the, ectodomain of MMP-14, respectively. A unique combination of the, above-described modifications produced the selective inhibitor, (2R)-N-[5-(4-bromophenyl)-6H-1,3,4-thiadiazin-2-yl]-2-[(phenylsulfonyl)ami, no]propanamide with high affinity for MMP-9 (K(i) = 40 nM). X-ray, crystallographic data obtained for cdMMP-8 cocrystallized with, N-allyl-5-(4-chlorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrobromide gave, detailed design information on binding interactions for thiadiazine-based, MMP inhibitors.
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<StructureSection load='1jh1' size='340' side='right'caption='[[1jh1]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1jh1]] 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=1JH1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1JH1 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]] 2.7&#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=JST:BUT-3-ENYL-[5-(4-CHLORO-PHENYL)-3,6-DIHYDRO-[1,3,4]THIADIAZIN-2-YLIDENE]-AMINE'>JST</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=1jh1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jh1 OCA], [https://pdbe.org/1jh1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1jh1 RCSB], [https://www.ebi.ac.uk/pdbsum/1jh1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1jh1 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/jh/1jh1_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=1jh1 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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1JH1 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=JST:'>JST</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=1JH1 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-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold., Schroder J, Henke A, Wenzel H, Brandstetter H, Stammler HG, Stammler A, Pfeiffer WD, Tschesche H, J Med Chem. 2001 Sep 27;44(20):3231-43. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11563922 11563922]
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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: Henke A]]
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[[Category: Henke, A.]]
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[[Category: Pfeiffer WD]]
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[[Category: Pfeiffer, W.D.]]
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[[Category: Schroder J]]
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[[Category: Schroder, J.]]
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[[Category: Stammler A]]
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[[Category: Stammler, A.]]
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[[Category: Stammler HG]]
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[[Category: Stammler, H.G.]]
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[[Category: Tschesche H]]
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[[Category: Tschesche, H.]]
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[[Category: Wenzel H]]
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[[Category: Wenzel, H.]]
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[[Category: CA]]
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[[Category: JST]]
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[[Category: ZN]]
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[[Category: collagenase]]
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[[Category: inhibitor]]
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[[Category: thiadiazine]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:07:24 2008''
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Current revision

Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor

PDB ID 1jh1

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