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PDBsum entry 2wuc
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Hydrolase/hydrolase inhibitor
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PDB id
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2wuc
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Contents |
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240 a.a.
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219 a.a.
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214 a.a.
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References listed in PDB file
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Key reference
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Title
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Unraveling the allosteric mechanism of serine protease inhibition by an antibody.
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Authors
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R.Ganesan,
C.Eigenbrot,
Y.Wu,
W.C.Liang,
S.Shia,
M.T.Lipari,
D.Kirchhofer.
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Ref.
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Structure, 2009,
17,
1614-1624.
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PubMed id
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Abstract
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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.
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