5th9: Difference between revisions
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==Structure determination of a potent, selective antibody inhibitor of human MMP9 (GS-5745 bound to MMP-9)== | |||
<StructureSection load='5th9' size='340' side='right'caption='[[5th9]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5th9]] is a 9 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TH9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TH9 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.999Å</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=NCO:COBALT+HEXAMMINE(III)'>NCO</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'>[https://proteopedia.org/fgij/fg.htm?mol=5th9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5th9 OCA], [https://pdbe.org/5th9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5th9 RCSB], [https://www.ebi.ac.uk/pdbsum/5th9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5th9 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[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 == | |||
[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;"> | |||
== Publication Abstract from PubMed == | |||
Matrix metalloproteinase 9 (MMP9) is a key regulator of the extracellular matrix (ECM), involved in the degradation of various ECM proteins. MMP9 is a member of a large family of proteases that are secreted as inactive zymogens. MMP9 plays a pathological role in a variety of inflammatory and oncology disorders and has long been considered an attractive therapeutic target. GS-5745 is a potent, highly selective humanized monoclonal antibody inhibitor of MMP9 that has shown promise in treating ulcerative colitis and gastric cancer. Here we describe the crystal structure of GS-5745:MMP9 complex and biochemical studies to elucidate the mechanism of GS-5745 inhibition of MMP9. GS-5745 binds MMP9 distal to the active site, near the junction between the prodomain and catalytic domain. GS-5745 inhibits MMP9 by two mechanisms: binding to active MMP9 allosterically inhibits MMP9 activity and binding to pro-MMP9 prevents MMP9 activation. | |||
Biochemical characterization and structure determination of a potent, selective antibody inhibitor of human MMP9.,Appleby TC, Greenstein AE, Hung M, Liclican A, Velasquez M, Villasenor AG, Wang R, Wong MH, Liu X, Papalia GA, Schultz BE, Sakowicz R, Smith V, Kwon HJ J Biol Chem. 2017 Feb 24. pii: jbc.M116.760579. doi: 10.1074/jbc.M116.760579. PMID:28235803<ref>PMID:28235803</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5th9" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Oryctolagus cuniculus]] | |||
[[Category: Appleby TC]] | |||
[[Category: Greenstein AE]] | |||
[[Category: Kwon HJ]] | |||
Latest revision as of 16:00, 4 October 2023
Structure determination of a potent, selective antibody inhibitor of human MMP9 (GS-5745 bound to MMP-9)Structure determination of a potent, selective antibody inhibitor of human MMP9 (GS-5745 bound to MMP-9)
Structural highlights
DiseaseMMP9_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. FunctionMMP9_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 PubMedMatrix metalloproteinase 9 (MMP9) is a key regulator of the extracellular matrix (ECM), involved in the degradation of various ECM proteins. MMP9 is a member of a large family of proteases that are secreted as inactive zymogens. MMP9 plays a pathological role in a variety of inflammatory and oncology disorders and has long been considered an attractive therapeutic target. GS-5745 is a potent, highly selective humanized monoclonal antibody inhibitor of MMP9 that has shown promise in treating ulcerative colitis and gastric cancer. Here we describe the crystal structure of GS-5745:MMP9 complex and biochemical studies to elucidate the mechanism of GS-5745 inhibition of MMP9. GS-5745 binds MMP9 distal to the active site, near the junction between the prodomain and catalytic domain. GS-5745 inhibits MMP9 by two mechanisms: binding to active MMP9 allosterically inhibits MMP9 activity and binding to pro-MMP9 prevents MMP9 activation. Biochemical characterization and structure determination of a potent, selective antibody inhibitor of human MMP9.,Appleby TC, Greenstein AE, Hung M, Liclican A, Velasquez M, Villasenor AG, Wang R, Wong MH, Liu X, Papalia GA, Schultz BE, Sakowicz R, Smith V, Kwon HJ J Biol Chem. 2017 Feb 24. pii: jbc.M116.760579. doi: 10.1074/jbc.M116.760579. PMID:28235803[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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