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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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PDB id:
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| Name: |
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Blood clotting/immune system
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Title:
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Hapc-h1573 fab complex
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Structure:
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Vitamin k-dependent protein c heavy chain. Chain: a, c, g. Synonym: anticoagulant protein c,autoprothrombin iia,blood coagulation factor xiv. Engineered: yes. Vitamin k-dependent protein c light chain. Chain: b, d, i. Synonym: anticoagulant protein c,autoprothrombin iia,blood coagulation factor xiv.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: proc. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_taxid: 10029
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Resolution:
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3.70Å
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R-factor:
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0.280
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R-free:
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0.302
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Authors:
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X.Wang,D.Wang,X.Zhao,U.Egner
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Key ref:
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X.Y.Zhao
et al.
(2020).
Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia.
Nat Commun,
11,
2992.
PubMed id:
DOI:
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Date:
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03-Mar-20
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Release date:
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08-Jul-20
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PROCHECK
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Headers
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References
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P04070
(PROC_HUMAN) -
Vitamin K-dependent protein C from Homo sapiens
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Seq:
Struc:
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461 a.a.
239 a.a.
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P04070
(PROC_HUMAN) -
Vitamin K-dependent protein C from Homo sapiens
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Seq:
Struc:
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461 a.a.
53 a.a.
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Enzyme class:
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Chains A, B, C, D, G, I:
E.C.3.4.21.69
- activated protein C (thrombin-activated peptidase).
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Reaction:
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Degradation of blood coagulation factors Va and VIIIa.
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DOI no:
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Nat Commun
11:2992
(2020)
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PubMed id:
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Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia.
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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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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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