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PDBsum entry 1nl0
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protein ligands metals Protein-protein interface(s) links
Immune system PDB id
1nl0

 

 

 

 

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Contents
Protein chains
213 a.a. *
216 a.a. *
45 a.a. *
Ligands
SO4
Metals
_CA ×6
Waters ×148
* Residue conservation analysis
PDB id:
1nl0
Name: Immune system
Title: Crystal structure of human factor ix gla domain in complex of an inhibitory antibody, 10c12
Structure: Anti-factor ix antibody, 10c12, chain l. Chain: l. Engineered: yes. Anti-factor ix antibody, 10c12, chain h. Chain: h. Engineered: yes. Factor ix. Chain: g. Fragment: gla domain.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: 10c12. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the protein was chemically synthesized. The sequence of the protein is naturally found in homo sapiens.
Biol. unit: Trimer (from PQS)
Resolution:
2.20Å     R-factor:   0.233     R-free:   0.270
Authors: M.Huang,B.C.Furie,B.Furie
Key ref:
M.Huang et al. (2004). Crystal structure of the calcium-stabilized human factor IX Gla domain bound to a conformation-specific anti-factor IX antibody. J Biol Chem, 279, 14338-14346. PubMed id: 14722079 DOI: 10.1074/jbc.M314011200
Date:
06-Jan-03     Release date:   20-Jan-04    
PROCHECK
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 Headers
 References

Protein chain
No UniProt id for this chain
Struc: 213 a.a.
Protein chain
No UniProt id for this chain
Struc: 216 a.a.
Protein chain
Pfam   ArchSchema ?
P00740  (FA9_HUMAN) -  Coagulation factor IX from Homo sapiens
Seq:
Struc: 		461 a.a.
45 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 12 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chain G: E.C.3.4.21.22  - coagulation factor IXa.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolyzes one Arg-|-Ile bond in factor X to form factor Xa.

 

 
DOI no: 10.1074/jbc.M314011200 J Biol Chem 279:14338-14346 (2004)
PubMed id: 14722079  
 
 
Crystal structure of the calcium-stabilized human factor IX Gla domain bound to a conformation-specific anti-factor IX antibody.
M.Huang, B.C.Furie, B.Furie.
 
  ABSTRACT  
 
The binding of Factor IX to membranes during blood coagulation is mediated by the N-terminal gamma-carboxyglutamic acid-rich (Gla) domain, a membrane-anchoring domain found on vitamin K-dependent blood coagulation and regulatory proteins. Conformation-specific anti-Factor IX antibodies are directed at the calcium-stabilized Gla domain and interfere with Factor IX-membrane interaction. One such antibody, 10C12, recognizes the calcium-stabilized form of the Gla domain of Factor IX. We prepared the fully carboxylated Gla domain of Factor IX by solid phase peptide synthesis and crystallized Factor IX-(1-47) in complex with Fab fragments of the 10C12 antibody. The overall structure of the Gla domain in the Factor IX-(1-47)-antibody complex at 2.2 A is similar to the structure of the Factor IX Gla domain in the presence of calcium ions as determined by NMR spectroscopy (Freedman, S. J., Furie, B. C., Furie, B., and Baleja, J. D. (1995) Biochemistry 34, 12126-12137) and by x-ray crystallography (Shikamoto, Y., Morita, T., Fujimoto, Z., and Mizuno, H. (2003) J. Biol. Chem. 278, 24090-24094). The complex structure shows that the complementarity determining region loops of the 10C12 antibody form a hydrophobic pocket to accommodate the hydrophobic patch of the Gla domain consisting of Leu-6, Phe-9, and Val-10. Polar interactions also play an important role in the antibody-antigen recognition. Furthermore, the calcium coordination network of the Factor IX Gla domain is different than in Gla domain structures of other vitamin K-dependent proteins. We conclude that this antibody is directed at the membrane binding site in the omega loop of Factor IX and blocks Factor IX function by inhibiting its interaction with membranes.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Crystal structure of the complex of the 10C12 Fab and Factor IX-(1-47). A ribbon diagram depicts the Fab fragment of the antibody 10C12. Light chain is shown in light blue, and heavy chain is shown in dark blue. Factor IX-(1-47) is also shown as a ribbon diagram, colored blue to yellow from the N terminus to the C terminus. Six calcium ions are shown from Ca-1 to Ca-7. Ca-6 is not present in this structure. Residues 1, 5, 6, 9, 11, and 45 in Factor IX-(1-47) are labeled. The side chains of residues 5, 6, 9, and 11 are included. 		Figure 6.
FIG. 6. Core calcium-ligand network in the Factor IX-(1-47)-calcium complex. The interatomic distances between oxygen ligands and calcium are shown as green dotted lines labeled with the distance in angstroms. The coordination of Ca-7, not located in the core calcium network, is not shown. The position of Ca-6 was not occupied in this crystal. Calcium ions (green); carbon (black); oxygen (red); nitrogen (blue).
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 14338-14346) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21239697 J.K.Tie, D.Y.Jin, D.L.Straight, and D.W.Stafford (2011).
Functional study of the vitamin K cycle in mammalian cells.
  Blood, 117, 2967-2974.  
20432072 B.Woodruff, B.Sullenger, and R.C.Becker (2010).
Antithrombotic therapy in acute coronary syndrome: how far up the coagulation cascade will we go?
  Curr Cardiol Rep, 12, 315-320.  
20419068 B.de Courcy, L.G.Pedersen, O.Parisel, N.Gresh, B.Silvi, J.Pilmé, and J.P.Piquemal (2010).
Understanding selectivity of hard and soft metal cations within biological systems using the subvalence concept. I. Application to blood coagulation: direct cation-protein electronic effects vs. indirect interactions through water networks.
  J Chem Theory Comput, 6, 1048-1063.  
20538861 M.Pancera, J.S.McLellan, X.Wu, J.Zhu, A.Changela, S.D.Schmidt, Y.Yang, T.Zhou, S.Phogat, J.R.Mascola, and P.D.Kwong (2010).
Crystal structure of PG16 and chimeric dissection with somatically related PG9: structure-function analysis of two quaternary-specific antibodies that effectively neutralize HIV-1.
  J Virol, 84, 8098-8110.
PDB codes: 3lrs 3mme
  20180816 Y.Z.Ohkubo, J.H.Morrissey, and E.Tajkhorshid (2010).
Dynamical view of membrane binding and complex formation of human factor VIIa and tissue factor.
  J Thromb Haemost, 8, 1044-1053.  
19133979 R.J.Preston, C.Morse, S.L.Murden, S.K.Brady, J.S.O'Donnell, and A.D.Mumford (2009).
The protein C omega-loop substitution Asn2Ile is associated with reduced protein C anticoagulant activity.
  Br J Haematol, 144, 946-953.  
19361276 T.Zögg, and H.Brandstetter (2009).
Activation mechanisms of coagulation factor IX.
  Biol Chem, 390, 391-400.  
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.  
18058827 R.E.Saunders, and S.J.Perkins (2008).
CoagMDB: a database analysis of missense mutations within four conserved domains in five vitamin K-dependent coagulation serine proteases using a text-mining tool.
  Hum Mutat, 29, 333-344.  
18540896 S.Mukherjee, A.Saha, P.Biswas, C.Mandal, and K.Ray (2008).
Structural analysis of factor IX protein variants to predict functional aberration causing haemophilia B.
  Haemophilia, 14, 1076-1081.  
17131117 O.Taboureau, and O.H.Olsen (2007).
Computational study of coagulation factor VIIa's affinity for phospholipid membranes.
  Eur Biophys J, 36, 133-144.  
17450328 R.C.Becker (2007).
Emergence of factor IXa as a target for pharmacologic inhibition: editors page.
  J Thromb Thrombolysis, 24, 81-83.  
15715678 B.Dahlbäck (2005).
Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases.
  J Intern Med, 257, 209-223.  
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.  
16011594 M.Mitchell, S.Keeney, and A.Goodeve (2005).
The molecular analysis of haemophilia B: a guideline from the UK haemophilia centre doctors' organization haemophilia genetics laboratory network.
  Haemophilia, 11, 398-404.  
15314527 M.Schenone, B.C.Furie, and B.Furie (2004).
The blood coagulation cascade.
  Curr Opin Hematol, 11, 272-277.  
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 codes are shown on the right.

 

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