PDBsum entry 7k66

Blood clotting/immune system

PDB id: 7k66

Contents

Protein chains

1265 a.a.

217 a.a.

213 a.a.

Ligands

NAG-NAG-BMA-MAN-MAN

NAG-NAG

NAG

Metals

_ZN

_CU

_CA

Waters ×1

PDB id:

7k66

Name:

Blood clotting/immune system

Title:

Structure of blood coagulation factor viii in complex with an anti-c1 domain pathogenic antibody inhibitor

Structure:

Coagulation factor viii,coagulation factor viii,coagulation factor viii,coagulation factor viii. Chain: a. Synonym: procoagulant component,antihemophilic factor,ahf, procoagulant component,procoagulant component,antihemophilic factor, ahf,procoagulant component. Engineered: yes. 2a9 heavy chain. Chain: b.

Source:

Sus scrofa, homo sapiens. Pig, human. Organism_taxid: 9823, 9606. Gene: f8, cf8, f8, f8c. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Mus musculus. Organism_taxid: 10090. Expressed in: mus musculus.

Resolution:

3.92Å R-factor: 0.234 R-free: 0.322

Authors:

K.C.Childers,J.Gish,L.Jarvis,S.Peters,C.Garrels,I.W.Smith, H.T.Spencer,P.C.Spiegel

Key ref:

J.S.Gish et al. (2021). Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor. Blood, 137, 2981-2986. PubMed id: 33529335

Date:

18-Sep-20 Release date: 14-Oct-20

Protein chain

P00451  (FA8_HUMAN) -  Coagulation factor VIII from Homo sapiens

Seq: 2351 a.a.

Struc: 1265 a.a.*

Protein chain

P12263  (FA8_PIG) -  Coagulation factor VIII from Sus scrofa

Seq: 2133 a.a.

Struc: 1265 a.a.*

Protein chain

No UniProt id for this chain

Struc: 217 a.a.

Protein chain

No UniProt id for this chain

Struc: 213 a.a.

* PDB and UniProt seqs differ at 159 residue positions (black crosses)

Blood 137:2981-2986 (2021)

PubMed id: 33529335

Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor.

J.S.Gish, L.Jarvis, K.C.Childers, S.C.Peters, C.S.Garrels, I.W.Smith, H.T.Spencer, C.B.Doering, P.Lollar, P.C.Spiegel.

ABSTRACT

Antibody inhibitor development in hemophilia A represents the most significant complication resulting from factor VIII (fVIII) replacement therapy. Recent studies have demonstrated that epitopes present in the C1 domain contribute to a pathogenic inhibitor response. In this study, we report the structure of a group A anti-C1 domain inhibitor, termed 2A9, in complex with a B domain-deleted, bioengineered fVIII construct (ET3i). The 2A9 epitope forms direct contacts to the C1 domain at 3 different surface loops consisting of Lys2065-Trp2070, Arg2150-Tyr2156, and Lys2110-Trp2112. Additional contacts are observed between 2A9 and the A3 domain, including the Phe1743-Tyr1748 loop and the N-linked glycosylation at Asn1810. Most of the C1 domain loops in the 2A9 epitope also represent a putative interface between fVIII and von Willebrand factor. Lastly, the C2 domain in the ET3i:2A9 complex adopts a large, novel conformational change, translocating outward from the structure of fVIII by 20 Å. This study reports the first structure of an anti-C1 domain antibody inhibitor and the first fVIII:inhibitor complex with a therapeutically active fVIII construct. Further structural understanding of fVIII immunogenicity may result in the development of more effective and safe fVIII replacement therapies.