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PDBsum entry 6aod
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Blood clotting/immune system
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PDB id
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6aod
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Contents |
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207 a.a.
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211 a.a.
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236 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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Structural basis for activity and specificity of an anticoagulant anti-Fxia monoclonal antibody and a reversal agent.
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Authors
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L.K.Ely,
M.Lolicato,
T.David,
K.Lowe,
Y.C.Kim,
D.Samuel,
P.Bessette,
J.L.Garcia,
T.Mikita,
D.L.Minor,
S.R.Coughlin.
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Ref.
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Structure, 2018,
26,
187.
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PubMed id
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Abstract
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Coagulation factor XIa is a candidate target for anticoagulants that better
separate antithrombotic efficacy from bleeding risk. We report a co-crystal
structure of the FXIa protease domain with DEF, a human monoclonal antibody that
blocks FXIa function and prevents thrombosis in animal models without detectable
increased bleeding. The light chain of DEF occludes the FXIa S1 subsite and
active site, while the heavy chain provides electrostatic interactions with the
surface of FXIa. The structure accounts for the specificity of DEF for FXIa over
its zymogen and related proteases, its active-site-dependent binding, and its
ability to inhibit substrate cleavage. The inactive FXIa protease domain used to
obtain the DEF-FXIa crystal structure reversed anticoagulant activity of DEF in
plasma and in vivo and the activity of a small-molecule FXIa active-site
inhibitor in vitro. DEF and this reversal agent for FXIa active-site inhibitors
may help support clinical development of FXIa-targeting anticoagulants.
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