2uwn

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spinqualitylabelsall models 2uwn, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF HUMAN COMPLEMENT FACTOR H, SCR DOMAINS 6-8 (H402 RISK VARIANT), IN COMPLEX WITH LIGAND.

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known diseases associated with this structure: Complement factor H deficiency OMIM:[134370], Factor H and factor H-like 1 OMIM:[134370], Hemolytic-uremic syndrome OMIM:[134370], Macular degeneration, age-related, 4 OMIM:[134370], Membranoproliferative glomerulonephritis with CFH deficiency OMIM:[134370]

About this Structure

2UWN 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.

Reference

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 Thu Feb 21 18:51:06 2008