6ekn: Difference between revisions
New page: '''Unreleased structure''' The entry 6ekn is ON HOLD Authors: Ciccone, L., Tepshi, L., Nuti, E., Rossello, A., Stura, E.A. Description: Crystal structure of MMP12 in complex with inhib... |
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==Crystal structure of MMP12 in complex with inhibitor BE7.== | |||
<StructureSection load='6ekn' size='340' side='right' caption='[[6ekn]], [[Resolution|resolution]] 1.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ekn]] 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=6EKN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EKN FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B9N:(2~{S})-2-[2-[4-(4-methoxyphenyl)phenyl]sulfonylphenyl]pentanedioic+acid'>B9N</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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">MMP12, HME ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6ekn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ekn OCA], [http://pdbe.org/6ekn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ekn RCSB], [http://www.ebi.ac.uk/pdbsum/6ekn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ekn ProSAT]</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 == | |||
Matrix metalloproteinase-12 (MMP-12) selective inhibitors could play a role in the treatment of lung inflammatory and cardiovascular diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl hydroxamate and carboxylate-based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12. In the newly synthesized thioaryl derivatives, the nature of the zinc binding group (ZBG) and the sulfur oxidation state were changed. Biological assays carried out in vitro on human MMPs with the resulting compounds led to identify a sulfide, 4a, bearing a N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. 4a is a promising hit compound since it displayed a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9, MMP-1 and MMP-14. Solution complexation studies with Zn2+ were performed to characterize the chelating abilities of the new compounds and confirmed the bidentate binding mode of HPD derivatives. X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains were carried out to rationalize the biological results. | |||
Development of Thioaryl-based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR and Crystallographic Studies.,Nuti E, Cuffaro D, Bernardini E, Camodeca C, Panelli L, Chaves S, Ciccone L, Tepshi L, Vera L, Orlandini E, Nencetti S, Stura EA, Santos MA, Dive V, Rossello A J Med Chem. 2018 May 4. doi: 10.1021/acs.jmedchem.8b00096. PMID:29727184<ref>PMID:29727184</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6ekn" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Macrophage elastase]] | |||
[[Category: Ciccone, L]] | [[Category: Ciccone, L]] | ||
[[Category: Nuti, E]] | |||
[[Category: Rossello, A]] | [[Category: Rossello, A]] | ||
[[Category: | [[Category: Stura, E A]] | ||
[[Category: Tepshi, L]] | [[Category: Tepshi, L]] | ||
[[Category: | [[Category: Carboxylate inhibitor alternative zinc-binding group]] | ||
[[Category: Hydrolase]] | |||
[[Category: Metzincin]] | |||
Latest revision as of 09:21, 6 June 2018
Crystal structure of MMP12 in complex with inhibitor BE7.Crystal structure of MMP12 in complex with inhibitor BE7.
Structural highlights
Function[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. Publication Abstract from PubMedMatrix metalloproteinase-12 (MMP-12) selective inhibitors could play a role in the treatment of lung inflammatory and cardiovascular diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl hydroxamate and carboxylate-based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12. In the newly synthesized thioaryl derivatives, the nature of the zinc binding group (ZBG) and the sulfur oxidation state were changed. Biological assays carried out in vitro on human MMPs with the resulting compounds led to identify a sulfide, 4a, bearing a N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. 4a is a promising hit compound since it displayed a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9, MMP-1 and MMP-14. Solution complexation studies with Zn2+ were performed to characterize the chelating abilities of the new compounds and confirmed the bidentate binding mode of HPD derivatives. X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains were carried out to rationalize the biological results. Development of Thioaryl-based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR and Crystallographic Studies.,Nuti E, Cuffaro D, Bernardini E, Camodeca C, Panelli L, Chaves S, Ciccone L, Tepshi L, Vera L, Orlandini E, Nencetti S, Stura EA, Santos MA, Dive V, Rossello A J Med Chem. 2018 May 4. doi: 10.1021/acs.jmedchem.8b00096. PMID:29727184[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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