8k5y

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Current revision (08:02, 6 December 2023) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 8k5y is ON HOLD until Paper Publication
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==Crystal structure of human proMMP-9 catalytic domain in complex with inhibitor==
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<StructureSection load='8k5y' size='340' side='right'caption='[[8k5y]], [[Resolution|resolution]] 1.52&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[8k5y]] is a 2 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=8K5Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8K5Y FirstGlance]. <br>
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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]] 1.52&#8491;</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=2HP:DIHYDROGENPHOSPHATE+ION'>2HP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=VP6:(3-azanyl-4-fluoranyl-5,7,8,9-tetrahydropyrido[4,3-c]azepin-6-yl)-[6-(2-oxidanylpropan-2-yl)-1H-indol-2-yl]methanone'>VP6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=8k5y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8k5y OCA], [https://pdbe.org/8k5y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8k5y RCSB], [https://www.ebi.ac.uk/pdbsum/8k5y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8k5y ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/MMP9_HUMAN MMP9_HUMAN] Defects in MMP9 may be a cause of susceptibility to intervertebral disc disease (IDD) [MIM:[https://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:[https://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.
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== Function ==
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[https://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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.
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Authors: Kamitani, M., Mima, M., Nishikawa-Shimono, R.
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Discovery of novel indole derivatives as potent and selective inhibitors of proMMP-9 activation.,Nishikawa-Shimono R, Kuwabara M, Fujisaki S, Matsuda D, Endo M, Kamitani M, Futamura A, Nomura Y, Yamaguchi-Sasaki T, Yabuuchi T, Yamaguchi C, Tanaka-Yamamoto N, Satake S, Abe-Sato K, Funayama K, Sakata M, Takahashi S, Hirano K, Fukunaga T, Uozumi Y, Kato S, Tamura Y, Nakamori T, Mima M, Mishima-Tsumagari C, Nozawa D, Imai Y, Asami T Bioorg Med Chem Lett. 2023 Nov 10;97:129541. doi: 10.1016/j.bmcl.2023.129541. PMID:37952596<ref>PMID:37952596</ref>
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Description: Crystal structure of human proMMP-9 catalytic domain in complex with inhibitor
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Mima, M]]
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<div class="pdbe-citations 8k5y" style="background-color:#fffaf0;"></div>
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[[Category: Nishikawa-Shimono, R]]
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== References ==
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[[Category: Kamitani, M]]
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Kamitani M]]
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[[Category: Mima M]]
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[[Category: Nishikawa-Shimono R]]

Current revision

Crystal structure of human proMMP-9 catalytic domain in complex with inhibitor

PDB ID 8k5y

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