4gr8: Difference between revisions
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==Crystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470C== | |||
<StructureSection load='4gr8' size='340' side='right' caption='[[4gr8]], [[Resolution|resolution]] 1.30Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4gr8]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GR8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GR8 FirstGlance]. <br> | |||
</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=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=R4C:N-{(2S)-3-[(R)-(4-BROMOPHENYL)(HYDROXY)PHOSPHORYL]-2-[(3-PHENYL-1,2-OXAZOL-5-YL)METHYL]PROPANOYL}-L-ALANYL-L-ALANINAMIDE'>R4C</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gr3|4gr3]], [[4gr0|4gr0]], [[4gql|4gql]], [[3lik|3lik]], [[3ljg|3ljg]], [[3lir|3lir]], [[3lil|3lil]], [[4efs|4efs]], [[3tsk|3tsk]], [[3ts4|3ts4]]</td></tr> | |||
<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 Homo sapiens])</td></tr> | |||
<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> | |||
<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=4gr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gr8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gr8 RCSB], [http://www.ebi.ac.uk/pdbsum/4gr8 PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The molecular determinants responsible for the potency of the RXP470.1 phosphinic peptide inhibitor towards matrix metalloprotease-12 (MMP-12) remain elusive. To address this issue, structure-activity study, X-ray crystallography and isothermal titration calorimetry (ITC) experiments were performed. The crystal structure of MMP-12/inhibitor complex (1.15 A) reveals that the inhibitor establishes multiple interactions with the MMP-12 active site, with its long P1' side chain filling most part of the S1' deep cavity. ITC experiments indicate that the binding of this inhibitor to MMP-12 is mostly entropy driven (DeltaG degrees = -13.1 kcal/mol, DeltaH degrees = -2.53 kcal/mol and -TDeltaS degrees = -10.60 kcal/mol) and involves a proton uptake from the buffer. Comparing phosphinic versus hydroxamate inhibitors reveals that the chelation of the zinc ion is slightly different, leading the inhibitor backbone to adopt a position in which the hydrogen bonding with the MMP-12 active site is less favorable in phosphinic inhibitor, while maintaining high affinity. | |||
Molecular determinants of a selective matrix metalloprotease-12 inhibitor: Insights from crystallography and thermodynamic studies.,Czarny B, Stura EA, Devel L, Vera L, Lajeunesse E, Beau F, Calderone V, Fragai M, Luchinat C, Dive V J Med Chem. 2013 Jan 23. PMID:23343195<ref>PMID:23343195</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Matrix metalloproteinase|Matrix metalloproteinase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Macrophage elastase]] | [[Category: Macrophage elastase]] | ||
[[Category: Beau, F | [[Category: Beau, F]] | ||
[[Category: Cassar-Lajeunesse, E | [[Category: Cassar-Lajeunesse, E]] | ||
[[Category: Devel, L | [[Category: Devel, L]] | ||
[[Category: Dive, V | [[Category: Dive, V]] | ||
[[Category: Stura, E A | [[Category: Stura, E A]] | ||
[[Category: Vera, L | [[Category: Vera, L]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Metzincin]] | [[Category: Metzincin]] | ||
[[Category: Potent selective phosphinic inhibitor]] | [[Category: Potent selective phosphinic inhibitor]] | ||
[[Category: Zinc protease]] | [[Category: Zinc protease]] | ||
