Biochemical characterization and structure determination of a potent, selective antibody inhibitor of human MMP9.
(2017) J Biol Chem 292: 6810-6820
Authors: 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.
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.
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