5TH9

Structure determination of a potent, selective antibody inhibitor of human MMP9 (GS-5745 bound to MMP-9)

5TH9 の概要

• エントリーDOI: 10.2210/pdb5th9/pdb
• 関連するPDBエントリー: 5TH6
• 分子名称: GS-5745 Fab light chain, GS-5745 Fab heavy chain, Matrix metalloproteinase-9,Matrix metalloproteinase-9, ... (7 entities in total)
• 機能のキーワード: metalloproteinase-9 antibody inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Oryctolagus cuniculus; 詳細
• 細胞内の位置: Secreted, extracellular space, extracellular matrix : P14780
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 223695.54

構造登録者

Appleby, T.C.,Greenstein, A.E.,Kwon, H.J. (登録日: 2016-09-29, 公開日: 2017-03-15, 最終更新日: 2024-11-20)

主引用文献

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

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: 28235803
DOI: 10.1074/jbc.M116.760579

実験手法

X-RAY DIFFRACTION (2.999 Å)