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Human transthyretin in complex with iododiflunisal: structural features associated with a potent amyloid inhibitor

AuthorsGales, Luis; Macebo-Ribeiro, Sandra; Arsequell, Gemma ; Valencia Parera, Gregorio; Saraiva, Maria João; Damas, Ana Margarida
KeywordsAmyloid fibril
Amyloid inhibitor
Complex crystal structure
Familial amyloidotic polyneuropathy
Issue Date3-Feb-2005
PublisherBiochemical Society
Portland Press
CitationBiochemical Journal 388(2): 615-621 (2005)
AbstractEx vivo and in vitro studies have revealed the remarkable amyloid inhibitory potency and specificity of iododiflunisal in relation to transthyretin [Almeida, Macedo, Cardoso, Alves, Valencia, Arsequell, Planas and Saraiva (2004) Biochem. J. 381, 351–356], a protein implicated in familial amyloidotic polyneuropathy. In the present paper, the crystal structure of transthyretin complexed with this diflunisal derivative is reported, which enables a detailed analysis of the protein–ligand interactions. Iododiflunisal binds very deep in the hormone-binding channel. The iodine substituent is tightly anchored into a pocket of the binding site and the fluorine atoms provide extra hydrophobic contacts with the protein. The carboxylate substituent is involved in an electrostatic interaction with the Nz of a lysine residue. Moreover, ligand-induced conformational alterations in the side chain of some residues result in the formation of new intersubunit hydrogen bonds. All these new interactions, induced by iododiflunisal, increase the stability of the tetramer impairing the formation of amyloid fibrils. The crystal structure of this complex opens perspectives for the design of more specific and effective drugs for familial amyloidotic polyneuropathy patients.
Description7 pages, 5 figures, 2 tables.-- PMID: 15689188 [PubMed].-- PMCID: PMC1138969.-- Printed version published Jun 1, 2005.
Publisher version (URL)http://dx.doi.org/10.1042/BJ20042035
Appears in Collections:(IQAC) Artículos
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