2WUC
Crystal structure of HGFA in complex with the allosteric non- inhibitory antibody Fab40.deltaTrp and Ac-KQLR-chloromethylketone
Summary for 2WUC
Entry DOI | 10.2210/pdb2wuc/pdb |
Related | 1YBW 1YC0 2WUB |
Related PRD ID | PRD_000307 |
Descriptor | HEPATOCYTE GROWTH FACTOR ACTIVATOR LONG CHAIN, HEPATOCYTE GROWTH FACTOR ACTIVATOR SHORT CHAIN, FAB FRAGMENT FAB40.DELTATRP HEAVY CHAIN, ... (7 entities in total) |
Functional Keywords | serine protease, egf-like domain, allosteric inhibitor, kringle, antibody, hydrolase, fab complex, glycoprotein, immune system, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
Biological source | HOMO SAPIENS (HUMAN) More |
Total number of polymer chains | 5 |
Total formula weight | 79799.03 |
Authors | Ganesan, R.,Eigenbrot, C.,Shia, S. (deposition date: 2009-10-01, release date: 2009-12-15, Last modification date: 2023-12-20) |
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 Cited by 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: 20004165DOI: 10.1016/J.STR.2009.09.014 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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