2UWN

Crystal structure of Human Complement Factor H, SCR domains 6-8 (H402 risk variant), in complex with ligand.

Summary for 2UWN

• Entry DOI: 10.2210/pdb2uwn/pdb
• Related: 1FHC 1HAQ 1HFH 1KOV 2G7I 2JGW 2JGX 2V8E
• Related PRD ID: PRD_900013
• Descriptor: HUMAN COMPLEMENT FACTOR H, 1,3,4,6-tetra-O-sulfo-beta-D-fructofuranose-(2-1)-2,3,4,6-tetra-O-sulfonato-alpha-D-glucopyranose, ACETATE ION, ... (6 entities in total)
• Functional Keywords: alternative splicing, sucrose octasulphate, age-related macular degeneration, complement alternate pathway, disease mutation, glycosaminoglycan, glycoprotein, innate immunity, immune response, sushi, factor h, complement, polymorphism, immune system
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Secreted: P08603
• Total number of polymer chains: 1
• Total formula weight: 22547.79

Authors

Prosser, B.E.,Johnson, S.,Roversi, P.,Herbert, A.P.,Blaum, B.S.,Tyrrell, J.,Jowitt, T.A.,Clark, S.J.,Terelli, E.,Uhrin, D.,Barlow, P.N.,Sim, R.B.,Day, A.J.,Lea, S.M. (deposition date: 2007-03-22, release date: 2007-10-02, Last modification date: 2023-12-13)

Primary citation

Prosser, B.E.,Johnson, S.,Roversi, P.,Herbert, A.P.,Blaum, B.S.,Tyrrell, J.,Jowitt, T.A.,Clark, S.J.,Tarelli, E.,Uhrin, D.,Barlow, P.N.,Sim, R.B.,Day, A.J.,Lea, S.M.
Structural Basis for Complement Factor H Linked Age-Related Macular Degeneration.
J.Exp.Med., 204:2277-, 2007

PubMed 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.

PubMed: 17893204
DOI: 10.1084/JEM.20071069

Experimental method

X-RAY DIFFRACTION (2.35 Å)