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PDBsum entry 6m3c
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Blood clotting/immune system
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PDB id
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6m3c
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Contents |
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239 a.a.
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53 a.a.
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218 a.a.
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221 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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Targeted inhibition of activated protein c by a non-Active-Site inhibitory antibody to treat hemophilia.
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Authors
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X.Y.Zhao,
A.Wilmen,
D.Wang,
X.Wang,
M.Bauzon,
J.Y.Kim,
L.Linden,
L.Li,
U.Egner,
T.Marquardt,
D.Moosmayer,
J.Tebbe,
J.M.Glück,
P.Ellinger,
K.Mclean,
S.Yuan,
S.Yegneswaran,
X.Jiang,
V.Evans,
J.M.Gu,
D.Schneider,
Y.Zhu,
Y.Xu,
C.Mallari,
A.Hesslein,
Y.Wang,
N.Schmidt,
K.Gutberlet,
C.Ruehl-Fehlert,
A.Freyberger,
T.Hermiston,
C.Patel,
D.Sim,
L.O.Mosnier,
V.Laux.
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Ref.
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Nat Commun, 2020,
11,
2992.
[DOI no: ]
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PubMed id
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Abstract
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Activated protein C (APC) is a plasma serine protease with antithrombotic and
cytoprotective functions. Based on the hypothesis that specific inhibition of
APC's anticoagulant but not its cytoprotective activity can be beneficial for
hemophilia therapy, 2 types of inhibitory monoclonal antibodies (mAbs) are
tested: A type I active-site binding mAb and a type II mAb binding to an exosite
on APC (required for anticoagulant activity) as shown by X-ray crystallography.
Both mAbs increase thrombin generation and promote plasma clotting. Type I
blocks all APC activities, whereas type II preserves APC's cytoprotective
function. In normal monkeys, type I causes many adverse effects including animal
death. In contrast, type II is well-tolerated in normal monkeys and shows both
acute and prophylactic dose-dependent efficacy in hemophilic monkeys. Our data
show that the type II mAb can specifically inhibit APC's anticoagulant function
without compromising its cytoprotective function and offers superior therapeutic
opportunities for hemophilia.
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