4i03

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==Human MMP12 in complex with a PEG-linked bifunctional L-glutamate motif inhibitor==
==Human MMP12 in complex with a PEG-linked bifunctional L-glutamate motif inhibitor==
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<StructureSection load='4i03' size='340' side='right' caption='[[4i03]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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<StructureSection load='4i03' size='340' side='right'caption='[[4i03]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4i03]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I03 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I03 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4i03]] 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=4I03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4I03 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=L88:(4R,22R)-5,21-DIOXO-4,22-BIS({3-[4-(4-PHENYLTHIOPHEN-2-YL)PHENYL]PROPANOYL}AMINO)-10,13,16-TRIOXA-6,20-DIAZAPENTACOSANE-1,25-DIOIC+ACID'>L88</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGO:S-1,2-PROPANEDIOL'>PGO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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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]] 1.7&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4efs|4efs]], [[3ts4|3ts4]], [[3tsk|3tsk]], [[4h30|4h30]], [[4h49|4h49]]</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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=L88:(4R,22R)-5,21-DIOXO-4,22-BIS({3-[4-(4-PHENYLTHIOPHEN-2-YL)PHENYL]PROPANOYL}AMINO)-10,13,16-TRIOXA-6,20-DIAZAPENTACOSANE-1,25-DIOIC+ACID'>L88</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGO:S-1,2-PROPANEDIOL'>PGO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HME, MMP12 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4i03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i03 OCA], [https://pdbe.org/4i03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4i03 RCSB], [https://www.ebi.ac.uk/pdbsum/4i03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4i03 ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Macrophage_elastase Macrophage elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.65 3.4.24.65] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4i03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i03 OCA], [http://pdbe.org/4i03 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4i03 RCSB], [http://www.ebi.ac.uk/pdbsum/4i03 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4i03 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/MMP12_HUMAN MMP12_HUMAN]] May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3.
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[https://www.uniprot.org/uniprot/MMP12_HUMAN MMP12_HUMAN] May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Homodimerization is important in signal transduction and can play a crucial role in many other biological systems. To obtaining structural information for the design of molecules able to control the signalization pathways, the proteins involved will have to be crystallized in complex with ligands that induce dimerization. Bi-functional drugs have been generated by linking two ligands together chemically and the relative crystallizability of complexes with mono-functional and bi-functional ligands has been evaluated. There are problems associated with crystallization with such ligands, but overall, the advantages appear to be greater than the drawbacks. The study involves two matrix metalloproteinases, MMP-12 and MMP-9. Using flexible and rigid linkers we show that it is possible to control the crystal packing and that by changing the ligand-enzyme stoichiometric ratio, one can toggle between having one bi-functional ligand binding to two enzymes and having the same ligand bound to each enzyme. The nature of linker and its point of attachment on the ligand can be varied to aid crystallization, and such variations can also provide valuable structural information about the interactions made by the linker with the protein. We report here the crystallization and structure determination of seven ligand-dimerized complexes. These results suggest that the use of bi-functional drugs can be extended beyond the realm of protein dimerization to include all drug design projects.
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Crystallization of bi-functional ligand protein complexes.,Antoni C, Vera L, Devel L, Catalani MP, Czarny B, Cassar-Lajeunesse E, Nuti E, Rossello A, Dive V, Stura EA J Struct Biol. 2013 Apr 6. pii: S1047-8477(13)00086-5. doi:, 10.1016/j.jsb.2013.03.015. PMID:23567804<ref>PMID:23567804</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4i03" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Matrix metalloproteinase|Matrix metalloproteinase]]
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*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Macrophage elastase]]
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[[Category: Large Structures]]
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[[Category: Cassar-Lajeunesse, E]]
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[[Category: Cassar-Lajeunesse E]]
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[[Category: Devel, L]]
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[[Category: Devel L]]
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[[Category: Dive, V]]
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[[Category: Dive V]]
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[[Category: Stura, E A]]
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[[Category: Stura EA]]
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[[Category: Vera, L]]
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[[Category: Vera L]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Metzincin]]
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[[Category: Selective carboxylate based mmp-12 bifunctional inhibitor]]
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[[Category: Zinc protease]]
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Current revision

Human MMP12 in complex with a PEG-linked bifunctional L-glutamate motif inhibitor

PDB ID 4i03

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