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PDBsum entry 4ki5
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Immune system
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PDB id
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4ki5
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Contents |
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218 a.a.
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211 a.a.
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224 a.a.
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209 a.a.
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154 a.a.
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PDB id:
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Immune system
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Title:
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Cystal structure of human factor viii c2 domain in a ternary complex with murine inhbitory antibodies 3e6 and g99
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Structure:
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Murine monoclonal 3e6 fab heavy chain. Chain: c. Murine monoclonal 3e6 fab light chain. Chain: d. Murine monoclonal g99 fab heavy chain. Chain: e. Murine monoclonal g99 fab light chain. Chain: f. Coagulation factor viii.
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Source:
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Mus musculus. Organism_taxid: 10090. Homo sapiens. Human. Organism_taxid: 9606. Gene: f8, f8c. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.47Å
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R-factor:
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0.190
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R-free:
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0.238
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Authors:
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J.D.Walter,S.L.Meeks,J.F.Healey,P.Lollar,P.C.Spiegel
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Key ref:
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J.D.Walter
et al.
(2013).
Structure of the factor VIII C2 domain in a ternary complex with 2 inhibitor antibodies reveals classical and nonclassical epitopes.
Blood,
122,
4270-4278.
PubMed id:
DOI:
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Date:
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01-May-13
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Release date:
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15-Jan-14
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PROCHECK
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Headers
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References
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No UniProt id for this chain
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No UniProt id for this chain
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No UniProt id for this chain
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DOI no:
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Blood
122:4270-4278
(2013)
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PubMed id:
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Structure of the factor VIII C2 domain in a ternary complex with 2 inhibitor antibodies reveals classical and nonclassical epitopes.
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J.D.Walter,
R.A.Werther,
C.M.Brison,
R.K.Cragerud,
J.F.Healey,
S.L.Meeks,
P.Lollar,
P.C.Spiegel.
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ABSTRACT
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The factor VIII C2 domain is a highly immunogenic domain, whereby inhibitory
antibodies develop following factor VIII replacement therapy for congenital
hemophilia A patients. Inhibitory antibodies also arise spontaneously in cases
of acquired hemophilia A. The structural basis for molecular recognition by 2
classes of anti-C2 inhibitory antibodies that bind to factor VIII simultaneously
was investigated by x-ray crystallography. The C2 domain/3E6 FAB/G99 FAB ternary
complex illustrates that each antibody recognizes epitopes on opposing faces of
the factor VIII C2 domain. The 3E6 epitope forms direct contacts to the C2
domain at 2 loops consisting of Glu2181-Ala2188 and Thr2202-Arg2215, whereas the
G99 epitope centers on Lys2227 and also makes direct contacts with loops
Gln2222-Trp2229, Leu2261-Ser2263, His2269-Val2282, and Arg2307-Gln2311. Each
binding interface is highly electrostatic, with positive charge present on both
C2 epitopes and complementary negative charge on each antibody. A new model of
membrane association is also presented, where the 3E6 epitope faces the
negatively charged membrane surface and Arg2320 is poised at the center of the
binding interface. These results illustrate the potential complexities of the
polyclonal anti-factor VIII immune response and further define the
"classical" and "nonclassical" types of antibody inhibitors
against the factor VIII C2 domain.
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