5TH9
Structure determination of a potent, selective antibody inhibitor of human MMP9 (GS-5745 bound to MMP-9)
Summary for 5TH9
| Entry DOI | 10.2210/pdb5th9/pdb |
| Related | 5TH6 |
| Descriptor | GS-5745 Fab light chain, GS-5745 Fab heavy chain, Matrix metalloproteinase-9,Matrix metalloproteinase-9, ... (7 entities in total) |
| Functional Keywords | metalloproteinase-9 antibody inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Oryctolagus cuniculus More |
| Cellular location | Secreted, extracellular space, extracellular matrix : P14780 |
| Total number of polymer chains | 9 |
| Total formula weight | 223695.54 |
| Authors | Appleby, T.C.,Greenstein, A.E.,Kwon, H.J. (deposition date: 2016-09-29, release date: 2017-03-15, Last modification date: 2024-11-20) |
| Primary citation | Appleby, T.C.,Greenstein, A.E.,Hung, M.,Liclican, A.,Velasquez, M.,Villasenor, A.G.,Wang, R.,Wong, M.H.,Liu, X.,Papalia, G.A.,Schultz, B.E.,Sakowicz, R.,Smith, V.,Kwon, H.J. Biochemical characterization and structure determination of a potent, selective antibody inhibitor of human MMP9. J. Biol. Chem., 292:6810-6820, 2017 Cited by PubMed Abstract: Matrix metalloproteinase 9 (MMP9) is a member of a large family of proteases that are secreted as inactive zymogens. It is a key regulator of the extracellular matrix, involved in the degradation of various extracellular matrix proteins. MMP9 plays a pathological role in a variety of inflammatory and oncology disorders and has long been considered an attractive therapeutic target. GS-5745, a potent, highly selective humanized monoclonal antibody inhibitor of MMP9, 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 inhibition of MMP9 by GS-5745. GS-5745 binds MMP9 distal to the active site, near the junction between the prodomain and catalytic domain, and inhibits MMP9 by two mechanisms. Binding to pro-MMP9 prevents MMP9 activation, whereas binding to active MMP9 allosterically inhibits activity. PubMed: 28235803DOI: 10.1074/jbc.M116.760579 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.999 Å) |
Structure validation
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