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PDBsum entry 2uwn
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protein ligands metals links
Immune system PDB id
2uwn

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
187 a.a. *
Ligands
GU4-YYJ
ACT
SO4 ×3
Metals
_CL ×2
Waters ×135
* Residue conservation analysis
PDB id:
2uwn
Name: Immune system
Title: Crystal structure of human complement factor h, scr domains 6-8 (h402 risk variant), in complex with ligand.
Structure: Human complement factor h. Chain: a. Fragment: domains 6,7 and 8, residues 322-506. Synonym: h factor 1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.35Å     R-factor:   0.214     R-free:   0.246
Authors: B.E.Prosser,S.Johnson,P.Roversi,A.P.Herbert,B.S.Blaum,J.Tyrrell, T.A.Jowitt,S.J.Clark,E.Terelli,D.Uhrin,P.N.Barlow,R.B.Sim,A.J.Day, S.M.Lea
Key ref: B.E.Prosser et al. (2007). Structural basis for complement factor H linked age-related macular degeneration. J Exp Med, 204, 2277-2283. PubMed id: 17893204
Date:
22-Mar-07     Release date:   02-Oct-07    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P08603  (CFAH_HUMAN) -  Complement factor H from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1231 a.a.
187 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 

 
J Exp Med 204:2277-2283 (2007)
PubMed id: 17893204  
 
 
Structural basis for complement factor H linked age-related macular degeneration.
B.E.Prosser, S.Johnson, P.Roversi, A.P.Herbert, B.S.Blaum, J.Tyrrell, T.A.Jowitt, S.J.Clark, E.Tarelli, D.Uhrín, P.N.Barlow, R.B.Sim, A.J.Day, S.M.Lea.
 
  ABSTRACT  
 
Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for the complement regulator factor H (FH), which causes a Tyr-to-His substitution at position 402, is linked to approximately 50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans (GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease-associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan-binding site occupies the center of an extended interaction groove on the regulator's surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure-based site-directed mutagenesis, nuclear magnetic resonance-monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG-FH complex.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21317894 H.P.Morgan, C.Q.Schmidt, M.Guariento, B.S.Blaum, D.Gillespie, A.P.Herbert, D.Kavanagh, H.D.Mertens, D.I.Svergun, C.M.Johansson, D.Uhrín, P.N.Barlow, and J.P.Hannan (2011).
Structural basis for engagement by complement factor H of C3b on a self surface.
  Nat Struct Mol Biol, 18, 463-470.
PDB code: 3oxu
21270465 I.C.Pechtl, D.Kavanagh, N.McIntosh, C.L.Harris, and P.N.Barlow (2011).
Disease-associated N-terminal complement factor H mutations perturb cofactor and decay-accelerating activities.
  J Biol Chem, 286, 11082-11090.  
21336275 P.Gros (2011).
In self-defense.
  Nat Struct Mol Biol, 18, 401-402.  
21396937 R.Nan, I.Farabella, F.F.Schumacher, A.Miller, J.Gor, A.C.Martin, D.T.Jones, I.Lengyel, and S.J.Perkins (2011).
Zinc binding to the Tyr402 and His402 allotypes of complement factor H: possible implications for age-related macular degeneration.
  J Mol Biol, 408, 714-735.  
20212494 A.F.Wright, C.F.Chakarova, M.M.Abd El-Aziz, and S.S.Bhattacharya (2010).
Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait.
  Nat Rev Genet, 11, 273-284.  
19835885 C.Q.Schmidt, A.P.Herbert, H.D.Mertens, M.Guariento, D.C.Soares, D.Uhrin, A.J.Rowe, D.I.Svergun, and P.N.Barlow (2010).
The central portion of factor H (modules 10-15) is compact and contains a structurally deviant CCP module.
  J Mol Biol, 395, 105-122.
PDB code: 2kms
20467445 D.Serruto, R.Rappuoli, M.Scarselli, P.Gros, and J.A.van Strijp (2010).
Molecular mechanisms of complement evasion: learning from staphylococci and meningococci.
  Nat Rev Microbiol, 8, 393-399.  
19825847 L.A.Hecker, A.O.Edwards, E.Ryu, N.Tosakulwong, K.H.Baratz, W.L.Brown, P.Charbel Issa, H.P.Scholl, B.Pollok-Kopp, K.E.Schmid-Kubista, K.R.Bailey, and M.Oppermann (2010).
Genetic control of the alternative pathway of complement in humans and age-related macular degeneration.
  Hum Mol Genet, 19, 209-215.  
20382995 P.Roversi, S.Johnson, and S.M.Lea (2010).
With phases: how two wrongs can sometimes make a right.
  Acta Crystallogr D Biol Crystallogr, 66, 420-425.  
19729381 A.Marson, D.E.Robinson, P.N.Brookes, B.Mulloy, M.Wiles, S.J.Clark, H.L.Fielder, L.J.Collinson, S.A.Cain, C.M.Kielty, S.McArthur, D.J.Buttle, R.D.Short, J.D.Whittle, and A.J.Day (2009).
Development of a microtiter plate-based glycosaminoglycan array for the investigation of glycosaminoglycan-protein interactions.
  Glycobiology, 19, 1537-1546.  
19587596 A.Y.Ting, T.K.Lee, and I.M.MacDonald (2009).
Genetics of age-related macular degeneration.
  Curr Opin Ophthalmol, 20, 369-376.  
19264882 B.Rohrer, Q.Long, B.Coughlin, R.B.Wilson, Y.Huang, F.Qiao, P.H.Tang, K.Kunchithapautham, G.S.Gilkeson, and S.Tomlinson (2009).
A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration.
  Invest Ophthalmol Vis Sci, 50, 3056-3064.  
19259132 J.Bergeron-Sawitzke, B.Gold, A.Olsh, S.Schlotterbeck, K.Lemon, K.Visvanathan, R.Allikmets, and M.Dean (2009).
Multilocus analysis of age-related macular degeneration.
  Eur J Hum Genet, 17, 1190-1199.  
19386604 J.M.Thurman, B.Renner, K.Kunchithapautham, V.P.Ferreira, M.K.Pangburn, Z.Ablonczy, S.Tomlinson, V.M.Holers, and B.Rohrer (2009).
Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury.
  J Biol Chem, 284, 16939-16947.  
19273554 J.Shaughnessy, L.A.Lewis, H.Jarva, and S.Ram (2009).
Functional comparison of the binding of factor H short consensus repeat 6 (SCR 6) to factor H binding protein from Neisseria meningitidis and the binding of factor H SCR 18 to 20 to Neisseria gonorrhoeae porin.
  Infect Immun, 77, 2094-2103.  
19503104 J.Wu, Y.Q.Wu, D.Ricklin, B.J.Janssen, J.D.Lambris, and P.Gros (2009).
Structure of complement fragment C3b-factor H and implications for host protection by complement regulators.
  Nat Immunol, 10, 728-733.
PDB code: 2wii
19225461 M.C.Schneider, B.E.Prosser, J.J.Caesar, E.Kugelberg, S.Li, Q.Zhang, S.Quoraishi, J.E.Lovett, J.E.Deane, R.B.Sim, P.Roversi, S.Johnson, C.M.Tang, and S.M.Lea (2009).
Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates.
  Nature, 458, 890-893.
PDB codes: 2w80 2w81
19667083 M.K.Liszewski, M.K.Leung, R.Hauhart, C.J.Fang, P.Bertram, and J.P.Atkinson (2009).
Smallpox inhibitor of complement enzymes (SPICE): dissecting functional sites and abrogating activity.
  J Immunol, 183, 3150-3159.  
19605402 S.J.Perkins, A.I.Okemefuna, R.Nan, K.Li, and A.Bonner (2009).
Constrained solution scattering modelling of human antibodies and complement proteins reveals novel biological insights.
  J R Soc Interface, 6, S679-S696.  
19454698 V.P.Ferreira, A.P.Herbert, C.Cortés, K.A.McKee, B.S.Blaum, S.T.Esswein, D.Uhrín, P.N.Barlow, M.K.Pangburn, and D.Kavanagh (2009).
The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome.
  J Immunol, 182, 7009-7018.  
20090210 Y.Qazi, S.Maddula, and B.K.Ambati (2009).
Mediators of ocular angiogenesis.
  J Genet, 88, 495-515.  
18493641 E.Gemma, O.Meyer, D.Uhrín, and A.N.Hulme (2008).
Enabling methodology for the end functionalization of glycosaminoglycan oligosaccharides.
  Mol Biosyst, 4, 481-495.  
18627465 K.Haapasalo, H.Jarva, T.Siljander, W.Tewodros, J.Vuopio-Varkila, and T.S.Jokiranta (2008).
Complement factor H allotype 402H is associated with increased C3b opsonization and phagocytosis of Streptococcus pyogenes.
  Mol Microbiol, 70, 583-594.  
18224273 K.K.Lau, R.J.Smith, P.C.Kolbeck, and L.Butani (2008).
Dense deposit disease and the factor H H402 allele.
  Clin Exp Nephrol, 12, 228-232.  
19388159 M.K.Pangburn, V.P.Ferreira, and C.Cortes (2008).
Discrimination between host and pathogens by the complement system.
  Vaccine, 26, I15-I21.  
18299834 M.Patel, and C.C.Chan (2008).
Immunopathological aspects of age-related macular degeneration.
  Semin Immunopathol, 30, 97.  
18821684 N.K.Banda, A.K.Wood, K.Takahashi, B.Levitt, P.M.Rudd, L.Royle, J.L.Abrahams, G.L.Stahl, V.M.Holers, and W.P.Arend (2008).
Initiation of the alternative pathway of murine complement by immune complexes is dependent on N-glycans in IgG antibodies.
  Arthritis Rheum, 58, 3081-3089.  
18299835 N.S.Bora, P.Jha, and P.S.Bora (2008).
The role of complement in ocular pathology.
  Semin Immunopathol, 30, 85-95.  
18786923 S.Hakobyan, C.L.Harris, C.W.van den Berg, M.C.Fernandez-Alonso, E.G.de Jorge, S.R.de Cordoba, G.Rivas, P.Mangione, M.B.Pepys, and B.P.Morgan (2008).
Complement factor H binds to denatured rather than to native pentameric C-reactive protein.
  J Biol Chem, 283, 30451-30460.  
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.

 

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