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| | ==Crystal structure of a hydroxamate based inhibitor EN140 in complex with the MMP-9 catalytic domain== | | ==Crystal structure of a hydroxamate based inhibitor EN140 in complex with the MMP-9 catalytic domain== |
| - | <StructureSection load='4wzv' size='340' side='right' caption='[[4wzv]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='4wzv' size='340' side='right'caption='[[4wzv]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wzv]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WZV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WZV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wzv]] 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=4WZV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WZV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AZI:AZIDE+ION'>AZI</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=E40:(2R)-4-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)-N-HYDROXY-2-{[(4-METHOXYBIPHENYL-4-YL)SULFONYL](PROPAN-2-YLOXY)AMINO}BUTANAMIDE'>E40</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGO:S-1,2-PROPANEDIOL'>PGO</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]] 1.65Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4h3x|4h3x]], [[4hma|4hma]], [[4h82|4h82]], [[4h1q|4h1q]], [[4h2e|4h2e]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AZI:AZIDE+ION'>AZI</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=E40:(2R)-4-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)-N-HYDROXY-2-{[(4-METHOXYBIPHENYL-4-YL)SULFONYL](PROPAN-2-YLOXY)AMINO}BUTANAMIDE'>E40</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGO:S-1,2-PROPANEDIOL'>PGO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=4wzv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wzv OCA], [http://pdbe.org/4wzv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wzv RCSB], [http://www.ebi.ac.uk/pdbsum/4wzv PDBsum]</span></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=4wzv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wzv OCA], [https://pdbe.org/4wzv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wzv RCSB], [https://www.ebi.ac.uk/pdbsum/4wzv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wzv ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == 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. | + | [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. |
| | == Function == | | == 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> | + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4wzv" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4wzv" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cassar-Lajeunesse, E]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Dive, V]] | + | [[Category: Large Structures]] |
| - | [[Category: Nuti, E]] | + | [[Category: Cassar-Lajeunesse E]] |
| - | [[Category: Rossello, A]] | + | [[Category: Dive V]] |
| - | [[Category: Stura, E A]] | + | [[Category: Nuti E]] |
| - | [[Category: Vera, L]] | + | [[Category: Rossello A]] |
| - | [[Category: Hydrolase]] | + | [[Category: Stura EA]] |
| - | [[Category: Mmp9 inhibitor complex]] | + | [[Category: Vera L]] |
| - | [[Category: Thyroid hormone-binding protein]]
| + | |
| Structural highlights
4wzv is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.65Å |
| Ligands: | , , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
MMP9_HUMAN Defects in MMP9 may be a cause of susceptibility to intervertebral disc disease (IDD) [MIM: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.[1] Defects in MMP9 are the cause of metaphyseal anadysplasia type 2 (MANDP2) [MIM: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
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.[2]
Publication Abstract from PubMed
Matrix metalloproteinases (MMPs) have been shown to be involved in tumor-induced angiogenesis. In particular, MMP-2, MMP-9 and MMP-14 have been reported to be crucial for tumor angiogenesis and the formation of metastasis, thus becoming attractive targets in cancer therapy. Here, we report our optimization effort to identify novel N-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward MMP-2, MMP-9 and MMP-14 with respect to the previously discovered compound 1. A new series of hydroxamates was designed, synthesized and tested for their anti-angiogenic activity using in vitro assays with human umbilical vein endothelial cells (HUVECs). A nanomolar MMP-2, MMP-9 and MMP-14 inhibitor was identified, compound 3, able to potently inhibit angiogenesis in vitro and also in vivo in the matrigel sponge assay in mice. Finally, X-ray crystallographic and docking studies were conducted for compound 3 in order to investigate its binding mode to MMP-9 and MMP-14.
N-O-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in vivo Antiangiogenic Activity.,Nuti E, Cantelmo AR, Gallo C, Bruno A, Bassani B, Camodeca C, Tuccinardi T, Vera L, Orlandini E, Nencetti S, Stura EA, Martinelli A, Dive V, Albini A, Rossello A J Med Chem. 2015 Aug 11. PMID:26263024[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hirose Y, Chiba K, Karasugi T, Nakajima M, Kawaguchi Y, Mikami Y, Furuichi T, Mio F, Miyake A, Miyamoto T, Ozaki K, Takahashi A, Mizuta H, Kubo T, Kimura T, Tanaka T, Toyama Y, Ikegawa S. A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation. Am J Hum Genet. 2008 May;82(5):1122-9. Epub 2008 May 1. PMID:18455130 doi:S0002-9297(08)00223-1
- ↑ Tschesche H, Knauper V, Kramer S, Michaelis J, Oberhoff R, Reinke H. Latent collagenase and gelatinase from human neutrophils and their activation. Matrix Suppl. 1992;1:245-55. PMID:1480034
- ↑ Nuti E, Cantelmo AR, Gallo C, Bruno A, Bassani B, Camodeca C, Tuccinardi T, Vera L, Orlandini E, Nencetti S, Stura EA, Martinelli A, Dive V, Albini A, Rossello A. N-O-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in vivo Antiangiogenic Activity. J Med Chem. 2015 Aug 11. PMID:26263024 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00367
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