6esm: Difference between revisions
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==Crystal structure of MMP9 in complex with inhibitor BE4.== | |||
<StructureSection load='6esm' size='340' side='right' caption='[[6esm]], [[Resolution|resolution]] 1.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6esm]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ESM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ESM FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B9Z:(2~{S})-2-[2-[4-(4-methoxyphenyl)phenyl]sulfanylphenyl]pentanedioic+acid'>B9Z</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PZE:PIPERAZINE'>PZE</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">[[5i12|5i12]], [[6ela|6ela]]</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=6esm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6esm OCA], [http://pdbe.org/6esm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6esm RCSB], [http://www.ebi.ac.uk/pdbsum/6esm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6esm ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/MMP9_HUMAN MMP9_HUMAN]] Defects in MMP9 may be a cause of susceptibility to intervertebral disc disease (IDD) [MIM:[http://omim.org/entry/603932 603932]]; also known as lumbar disk herniation (LDH). IDD is one of the most common musculo-skeletal disorders and the predominant cause of low-back pain and unilateral leg pain.<ref>PMID:18455130</ref> Defects in MMP9 are the cause of metaphyseal anadysplasia type 2 (MANDP2) [MIM:[http://omim.org/entry/613073 613073]]. Metaphyseal anadysplasia consists of an abnormal bone development characterized by severe skeletal changes that, in contrast with the progressive course of most other skeletal dysplasias, resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia. | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/MMP9_HUMAN MMP9_HUMAN]] May play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. Could play a role in bone osteoclastic resorption. Cleaves KiSS1 at a Gly-|-Leu bond. Cleaves type IV and type V collagen into large C-terminal three quarter fragments and shorter N-terminal one quarter fragments. Degrades fibronectin but not laminin or Pz-peptide.<ref>PMID:1480034</ref> | |||
<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> | |||
</div> | |||
<div class="pdbe-citations 6esm" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[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]] | |||