2WUC: Crystal Structure Of Hgfa In Complex With The Allosteric Non- Inhibitory Antibody Fab40.deltatrp And Ac-kqlr-chloromethylketone

Citation:
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.
PDB ID: 2WUCDownload
MMDB ID: 94139
PDB Deposition Date: 2009/10/1
Updated in MMDB: 2016/12
Experimental Method:
x-ray diffraction
Resolution: 2.7  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 2WUC: pentameric; determined by author and by software (PISA)
Molecular Components in 2WUC
Label Count Molecule
Proteins (5 molecules)
1
Hepatocyte Growth Factor Activator Long Chain(Gene symbol: HGFAC)
Molecule annotation
1
Hepatocyte Growth Factor Activator Short Chain(Gene symbol: HGFAC)
Molecule annotation
1
FAB Fragment Fab40.deltatrp Heavy Chain
Molecule annotation
1
Ace-kqlr-chloromethylketone Inhibitor
Molecule annotation
1
FAB Fragment Fab40.deltatrp Light Chain
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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