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PDBsum entry 4xfn
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Protein fibril
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PDB id
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4xfn
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References listed in PDB file
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Key reference
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Title
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Uncovering the mechanism of aggregation of human transthyretin.
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Authors
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L.Saelices,
L.M.Johnson,
W.Y.Liang,
M.R.Sawaya,
D.Cascio,
P.Ruchala,
J.Whitelegge,
L.Jiang,
R.Riek,
D.S.Eisenberg.
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Ref.
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J Biol Chem, 2015,
290,
28932-28943.
[DOI no: ]
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PubMed id
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Abstract
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The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid
fibrils upon dissociation and monomer unfolding. The aggregation of
transthyretin has been reported as the cause of the life-threatening
transthyretin amyloidosis. The standard treatment of familial cases of TTR
amyloidosis has been liver transplantation. Although aggregation-preventing
strategies involving ligands are known, understanding the mechanism of TTR
aggregation can lead to additional inhibition approaches. Several models of TTR
amyloid fibrils have been proposed, but the segments that drive aggregation of
the protein have remained unknown. Here we identify β-strands F and H as
necessary for TTR aggregation. Based on the crystal structures of these
segments, we designed two non-natural peptide inhibitors that block aggregation.
This work provides the first characterization of peptide inhibitors for TTR
aggregation, establishing a novel therapeutic strategy.
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Headers
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