2WUB

Crystal structure of HGFA in complex with the allosteric non- inhibitory antibody Fab40.deltaTrp

Summary for 2WUB

• Entry DOI: 10.2210/pdb2wub/pdb
• Related: 1YBW 1YC0 2WUC
• Descriptor: HEPATOCYTE GROWTH FACTOR ACTIVATOR LONG CHAIN, HEPATOCYTE GROWTH FACTOR ACTIVATOR SHORT CHAIN, FAB FRAGMENT FAB40.DELTATRP HEAVY CHAIN, ... (6 entities in total)
• Functional Keywords: hydrolase immune system complex, disulfide bond, serine protease, egf-like domain, allosteric inhibitor, kringle, zymogen, protease, secreted, antibody, hydrolase, fab complex, polymorphism, glycoprotein, hydrolase-immune system complex, hydrolase/immune system
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 8
• Total formula weight: 158709.95

Authors

Ganesan, R.,Eigenbrot, C.,Shia, S. (deposition date: 2009-10-01, release date: 2009-12-15, Last modification date: 2024-10-23)

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-, 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 (2.9 Å)