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

AutorGales, Luis; Macebo-Ribeiro, Sandra; Arsequell, Gemma; Valencia Parera, Gregorio; Saraiva, Maria João; Damas, Ana Margarida
Palabras claveAmyloid fibril
Amyloid inhibitor
Complex crystal structure
Familial amyloidotic polyneuropathy
Fecha de publicación3-feb-2005
EditorBiochemical Society
Portland Press
CitaciónBiochemical Journal 388(2): 615-621 (2005)
ResumenEx 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.
Descripción7 pages, 5 figures, 2 tables.-- PMID: 15689188 [PubMed].-- PMCID: PMC1138969.-- Printed version published Jun 1, 2005.
Versión del editorhttp://dx.doi.org/10.1042/BJ20042035
ISSN0264-6021 (Print)
1470-8728 (Online)
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