3K2U

Crystal structure of HGFA in complex with the allosteric inhibitory antibody Fab40

Summary for 3K2U

• Entry DOI: 10.2210/pdb3k2u/pdb
• Related: 1YBW 1YC0 2R0K 2R0L
• Descriptor: Hepatocyte growth factor activator long chain, Hepatocyte growth factor activator short chain, Antibody, Fab fragment, Heavy Chain, ... (6 entities in total)
• Functional Keywords: serine protease, allosteric inhibitor, antibody, egf-like domain, glycoprotein, fab complex, hydrolase, disulfide bond, kringle, protease, secreted, zymogen, hydrolase-immune system complex, hydrolase/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 79379.04

Authors

Ganesan, R.,Eigenbrot, C.,Shia, S. (deposition date: 2009-09-30, release date: 2009-12-15, Last modification date: 2023-09-06)

Primary citation

Ganesan, R.,Eigenbrot, C.,Wu, Y.,Liang, W.C.,Shia, S.,Lipari, M.T.,Kirchhofer, D.
Unraveling the allosteric mechanism of serine protease inhibition by an antibody.
Structure, 17:1614-1624, 2009

PubMed Abstract: Recent structural studies have outlined the mechanism of protease inhibition by active site-directed antibodies. However, the molecular basis of allosteric inhibition by antibodies has been elusive. Here we report the 2.35 A resolution structure of the trypsin-like serine protease hepatocyte growth factor activator (HGFA) in complex with the allosteric antibody Ab40, a potent inhibitor of HGFA catalytic activity. The antibody binds at the periphery of the substrate binding cleft and imposes a conformational change on the entire 99-loop (chymotrypsinogen numbering). The altered conformation of the 99-loop is incompatible with substrate binding due to the partial collapse of subsite S2 and the reorganization of subsite S4. Remarkably, a single residue deletion of Ab40 abolished inhibition of HGFA activity, commensurate with the reversal of the 99-loop conformation to its "competent" state. The results define an "allosteric switch" mechanism as the basis of protease inhibition by an allosteric antibody.

PubMed: 20004165
DOI: 10.1016/j.str.2009.09.014

Experimental method

X-RAY DIFFRACTION (2.35 Å)