2v8e
CRYSTAL STRUCTURE OF HUMAN COMPLEMENT FACTOR H, SCR DOMAINS 6-8 (H402 RISK VARIANT), IN COMPLEX WITH LIGAND.
|
OverviewOverview
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.
About this StructureAbout this Structure
2V8E is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for complement factor H linked age-related macular degeneration., Prosser BE, Johnson S, Roversi P, Herbert AP, Blaum BS, Tyrrell J, Jowitt TA, Clark SJ, Tarelli E, Uhrin D, Barlow PN, Sim RB, Day AJ, Lea SM, J Exp Med. 2007 Oct 1;204(10):2277-83. Epub 2007 Sep 24. PMID:17893204
Page seeded by OCA on Wed Jan 23 12:51:33 2008