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4D7B

Structure of human transthyretin in complex with Tolcapone

Summary for 4D7B
Entry DOI10.2210/pdb4d7b/pdb
DescriptorTRANSTHYRETIN, Tolcapone (3 entities in total)
Functional Keywordstransport protein, amyloidogenesis
Biological sourceHOMO SAPIENS (HUMAN)
Cellular locationSecreted: P02766
Total number of polymer chains2
Total formula weight28363.60
Authors
Gallego, P.,Sant'anna, R.O.,Ventura, S.,Reverter, D. (deposition date: 2014-11-21, release date: 2016-01-20, Last modification date: 2024-05-08)
Primary citationReverter, D.,Gallego, P.,Santana, R.,Ventura, S.
Repositioning Tolcapone as a Potent Inhibitor of Transthyretin Amyloidogenesis and its Associated Cellular Toxicity
Nat.Commun., 7:10787-, 2016
Cited by
PubMed Abstract: Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists.
PubMed: 26902880
DOI: 10.1038/NCOMMS10787
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.15 Å)
Structure validation

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