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PDBsum entry 2uwn
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Immune system
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PDB id
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2uwn
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References listed in PDB file
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Key reference
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Title
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Structural basis for complement factor h linked age-Related macular degeneration.
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Authors
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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.
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Ref.
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J Exp Med, 2007,
204,
2277-2283.
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PubMed id
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Abstract
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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.
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