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Immune system/blood clotting PDB id
1iqd
Jmol
Contents
Protein chains
208 a.a. *
200 a.a. *
156 a.a. *
Waters ×477
* Residue conservation analysis
PDB id:
1iqd
Name: Immune system/blood clotting
Title: Human factor viii c2 domain complexed to human monoclonal bo2c11 fab.
Structure: Human monoclonal bo2c11 fab light chain. Chain: a. Human monoclonal bo2c11 fab heavy chain. Chain: b. Human factor viii. Chain: c. Fragment: c-terminal domain. Synonym: coagulation factor vii. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Strain: bo2c11. Expressed in: pichia pastoris. Expression_system_taxid: 4922.
Biol. unit: Trimer (from PQS)
Resolution:
2.00Å     R-factor:   0.203     R-free:   0.253
Authors: P.C.Spiegel Jr.,M.Jacquemin,J.M.Saint-Remy,B.L.Stoddard, K.P.Pratt
Key ref: P.C.Spiegel et al. (2001). Structure of a factor VIII C2 domain-immunoglobulin G4kappa Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII. Blood, 98, 13-19. PubMed id: 11418455 DOI: 10.1182/blood.V98.1.13
Date:
21-Jul-01     Release date:   15-Aug-01    
PROCHECK
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 Headers
 References

Protein chain
No UniProt id for this chain
Protein chain
No UniProt id for this chain
Protein chain
Pfam   ArchSchema ?
P00451  (FA8_HUMAN) -  Coagulation factor VIII
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		2351 a.a.
156 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     cell adhesion   2 terms 
  Biochemical function     protein binding     1 term  

 

 
DOI no: 10.1182/blood.V98.1.13 Blood 98:13-19 (2001)
PubMed id: 11418455  
 
 
Structure of a factor VIII C2 domain-immunoglobulin G4kappa Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII.
P.C.Spiegel, M.Jacquemin, J.M.Saint-Remy, B.L.Stoddard, K.P.Pratt.
 
  ABSTRACT  
 
The development of an immune response to infused factor VIII is a complication affecting many patients with hemophilia A. Inhibitor antibodies bind to antigenic determinants on the factor VIII molecule and block its procoagulant activity. A patient-derived inhibitory immunoglobulin G4kappa antibody (BO2C11) produced by an immortalized memory B-lymphocyte cell line interferes with the binding of factor VIII to phospholipid surfaces and to von Willebrand factor. The structure of a Fab fragment derived from this antibody complexed with the factor VIII C2 domain was determined at 2.0 A resolution. The Fab interacts with solvent-exposed basic and hydrophobic side chains that form a membrane-association surface of factor VIII. This atomic resolution structure suggests a variety of amino acid substitutions in the C2 domain of factor VIII that might prevent the binding of anti-C2 inhibitor antibodies without significantly compromising the procoagulant functions of factor VIII.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21156843 J.Lü, S.W.Pipe, H.Miao, M.Jacquemin, and G.E.Gilbert (2011).
A membrane-interactive surface on the factor VIII C1 domain cooperates with the C2 domain for cofactor function.
  Blood, 117, 3181-3189.  
21213247 P.L.Kastritis, I.H.Moal, H.Hwang, Z.Weng, P.A.Bates, A.M.Bonvin, and J.Janin (2011).
A structure-based benchmark for protein-protein binding affinity.
  Protein Sci, 20, 482-491.  
21210768 V.A.Novakovic, D.B.Cullinan, H.Wakabayashi, P.J.Fay, J.D.Baleja, and G.E.Gilbert (2011).
Membrane-binding properties of the Factor VIII C2 domain.
  Biochem J, 435, 187-196.  
20491952 P.M.van Helden, P.H.Kaijen, E.P.Mauser-Bunschoten, K.Fischer, H.M.van den Berg, and J.Voorberg (2010).
Domain specificity of factor VIII inhibitors during immune tolerance induction in patients with haemophilia A.
  Haemophilia, 16, 892-901.  
19199081 A.H.Zhang, J.Skupsky, and D.W.Scott (2009).
Factor VIII inhibitors: risk factors and methods for prevention and immune modulation.
  Clin Rev Allergy Immunol, 37, 114-124.  
19473423 A.Markoff, V.Gerke, and N.Bogdanova (2009).
Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function.
  Haemophilia, 15, 932-941.  
19172415 G.Lavigne-Lissalde, C.Rothschild, C.Pouplard, P.Lapalud, Y.Gruel, J.F.Schved, and C.Granier (2009).
Characteristics, mechanisms of action, and epitope mapping of anti-factor VIII antibodies.
  Clin Rev Allergy Immunol, 37, 67-79.  
19687511 H.Meems, A.B.Meijer, D.B.Cullinan, K.Mertens, and G.E.Gilbert (2009).
Factor VIII C1 domain residues Lys 2092 and Phe 2093 contribute to membrane binding and cofactor activity.
  Blood, 114, 3938-3946.  
  19572065 J.F.Healey, E.T.Parker, R.T.Barrow, T.J.Langley, W.R.Church, and P.Lollar (2009).
The comparative immunogenicity of human and porcine factor VIII in haemophilia A mice.
  Thromb Haemost, 102, 35-41.  
19184559 K.P.Pratt, and A.R.Thompson (2009).
B-cell and T-cell epitopes in anti-factor VIII immune responses.
  Clin Rev Allergy Immunol, 37, 80-95.  
  20140073 S.S.Negi, and W.Braun (2009).
Automated detection of conformational epitopes using phage display Peptide sequences.
  Bioinform Biol Insights, 3, 71-81.  
18184865 A.Venceslá, M.A.Corral-Rodríguez, M.Baena, M.Cornet, M.Domènech, M.Baiget, P.Fuentes-Prior, and E.F.Tizzano (2008).
Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites.
  Blood, 111, 3468-3478.  
17965321 B.W.Shen, P.C.Spiegel, C.H.Chang, J.W.Huh, J.S.Lee, J.Kim, Y.H.Kim, and B.L.Stoddard (2008).
The tertiary structure and domain organization of coagulation factor VIII.
  Blood, 111, 1240-1247.
PDB code: 2r7e
18045240 P.Stafford, C.Ghevaert, K.Campbell, C.Proulx, G.Smith, L.M.Williamson, E.Ranasinghe, N.A.Watkins, J.A.Huntington, and W.H.Ouwehand (2008).
Immunologic and structural analysis of eight novel domain-deletion beta(3) integrin peptides designed for detection of HPA-1 antibodies.
  J Thromb Haemost, 6, 366-375.  
18495957 S.L.Meeks, J.F.Healey, E.T.Parker, R.T.Barrow, and P.Lollar (2008).
Nonclassical anti-C2 domain antibodies are present in patients with factor VIII inhibitors.
  Blood, 112, 1151-1153.  
18337255 S.Planque, M.A.Escobar, K.C.Smith, H.Taguchi, Y.Nishiyama, E.Donnachie, K.P.Pratt, and S.Paul (2008).
Covalent inactivation of factor VIII antibodies from hemophilia A patients by an electrophilic FVIII Analog.
  J Biol Chem, 283, 11876-11886.  
18234071 V.Moreau, C.Fleury, D.Piquer, C.Nguyen, N.Novali, S.Villard, D.Laune, C.Granier, and F.Molina (2008).
PEPOP: computational design of immunogenic peptides.
  BMC Bioinformatics, 9, 71.  
17427229 E.M.Bublil, N.T.Freund, I.Mayrose, O.Penn, A.Roitburd-Berman, N.D.Rubinstein, T.Pupko, and J.M.Gershoni (2007).
Stepwise prediction of conformational discontinuous B-cell epitopes using the Mapitope algorithm.
  Proteins, 68, 294-304.  
17848617 S.L.Meeks, J.F.Healey, E.T.Parker, R.T.Barrow, and P.Lollar (2007).
Antihuman factor VIII C2 domain antibodies in hemophilia A mice recognize a functionally complex continuous spectrum of epitopes dominated by inhibitors of factor VIII activation.
  Blood, 110, 4234-4242.  
16472025 T.Hohm, P.Limbourg, and D.Hoffmann (2006).
A multiobjective evolutionary method for the design of peptidic mimotopes.
  J Comput Biol, 13, 113-125.  
16434442 V.Moreau, C.Granier, S.Villard, D.Laune, and F.Molina (2006).
Discontinuous epitope prediction based on mimotope analysis.
  Bioinformatics, 22, 1088-1095.  
16102111 L.Autin, M.A.Miteva, W.H.Lee, K.Mertens, K.P.Radtke, and B.O.Villoutreix (2005).
Molecular models of the procoagulant factor VIIIa-factor IXa complex.
  J Thromb Haemost, 3, 2044-2056.  
15572214 P.J.Fay, and P.V.Jenkins (2005).
Mutating factor VIII: lessons from structure to function.
  Blood Rev, 19, 15-27.  
15005336 B.Dahlbäck (2004).
Progress in the understanding of the protein C anticoagulant pathway.
  Int J Hematol, 79, 109-116.  
15257012 M.G.Jacquemin, and J.M.Saint-Remy (2004).
Factor VIII alloantibodies in hemophilia.
  Curr Opin Hematol, 11, 146-150.  
15489168 P.C.Spiegel, S.M.Kaiser, J.A.Simon, and B.L.Stoddard (2004).
Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII.
  Chem Biol, 11, 1413-1422.  
15219191 P.Lollar (2004).
Pathogenic antibodies to coagulation factors. Part one: factor VIII and factor IX.
  J Thromb Haemost, 2, 1082-1095.  
14962380 R.L.Stanfield, M.K.Gorny, C.Williams, S.Zolla-Pazner, and I.A.Wilson (2004).
Structural rationale for the broad neutralization of HIV-1 by human monoclonal antibody 447-52D.
  Structure, 12, 193-204.
PDB code: 1q1j
15479373 S.W.Pipe, J.M.Saint-Remy, and C.E.Walsh (2004).
New high-technology products for the treatment of haemophilia.
  Haemophilia, 10, 55-63.  
12871288 B.Dahlbäck, and B.O.Villoutreix (2003).
Molecular recognition in the protein C anticoagulant pathway.
  J Thromb Haemost, 1, 1525-1534.  
12945878 D.A.Lewis, K.D.Moore, and T.L.Ortel (2003).
Binding of factor VIII inhibitors to discrete regions of the factor VIII C2 domain disrupt phospholipid binding.
  Blood Coagul Fibrinolysis, 14, 361-368.  
12911593 M.T.Reding, D.K.Okita, B.M.Diethelm-Okita, T.A.Anderson, and B.M.Conti-Fine (2003).
Human CD4+ T-cell epitope repertoire on the C2 domain of coagulation factor VIII.
  J Thromb Haemost, 1, 1777-1784.  
12010424 D.Dimichele (2002).
Inhibitors: resolving diagnostic and therapeutic dilemmas.
  Haemophilia, 8, 280-287.  
12447901 P.A.Ramsland, and W.Farrugia (2002).
Crystal structures of human antibodies: a detailed and unfinished tapestry of immunoglobulin gene products.
  J Mol Recognit, 15, 248-259.  
  12617176 P.Lollar (2002).
Molecular characterization of the immune response to factor VIII.
  Vox Sang, 83, 403-408.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.