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==Crystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470B==
==Crystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470B==
<StructureSection load='4gr0' size='340' side='right' caption='[[4gr0]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
<StructureSection load='4gr0' size='340' side='right'caption='[[4gr0]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4gr0]] 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=4GR0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GR0 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4gr0]] 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=4GR0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GR0 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=R4B:N-[(2S)-3-[(R)-(4-BROMOPHENYL)(HYDROXY)PHOSPHORYL]-2-{[3-(3-CHLOROBIPHENYL-4-YL)-1,2-OXAZOL-5-YL]METHYL}PROPANOYL]-L-ALANYL-L-ALANINAMIDE'>R4B</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.497&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gql|4gql]], [[3lik|3lik]], [[3ljg|3ljg]], [[3lir|3lir]], [[3lil|3lil]], [[4efs|4efs]], [[3tsk|3tsk]], [[3ts4|3ts4]], [[4gr3|4gr3]], [[4gr8|4gr8]]</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=R4B:N-[(2S)-3-[(R)-(4-BROMOPHENYL)(HYDROXY)PHOSPHORYL]-2-{[3-(3-CHLOROBIPHENYL-4-YL)-1,2-OXAZOL-5-YL]METHYL}PROPANOYL]-L-ALANYL-L-ALANINAMIDE'>R4B</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4gr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gr0 OCA], [https://pdbe.org/4gr0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gr0 RCSB], [https://www.ebi.ac.uk/pdbsum/4gr0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gr0 ProSAT]</span></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=4gr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gr0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gr0 RCSB], [http://www.ebi.ac.uk/pdbsum/4gr0 PDBsum]</span></td></tr>
</table>
</table>
== Function ==
== 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.  
[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.
<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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>


==See Also==
==See Also==
*[[Matrix metalloproteinase|Matrix metalloproteinase]]
*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Macrophage elastase]]
[[Category: Large Structures]]
[[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 EA]]
[[Category: Vera, L]]
[[Category: Vera L]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Metzincin]]
[[Category: Potent selective phosphinic inhibitor]]
[[Category: Zinc protease]]
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