Human transthyretin in complex with iododiflunisal: structural features associated with a potent amyloid inhibitor
| Autor: | Sandra Macedo-Ribeiro, A. M. Damas, Maria João Saraiva, Luís Gales, Gregorio Valencia, Gemma Arsequell |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
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Models
Molecular Amyloid Stereochemistry Plasma protein binding Biochemistry Amyloid inhibitor Transthyretin Tetramer Molecule Humans Prealbumin Familial amyloidotic polyneuropathy Binding site Molecular Biology Amyloid fibrils Binding Sites biology Molecular Structure Chemistry Hydrogen bond Cell Biology Diflunisal Transport protein Complex crystal structure biology.protein Iododiflunisal Protein Binding Research Article |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | 7 pages, 5 figures, 2 tables.-- PMID: 15689188 [PubMed].-- PMCID: PMC1138969.-- Printed version published Jun 1, 2005. Ex 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. Financial support from FCT (Fundação para a Ciência e a Tecnologia, Lisboa, Portugal) (project POCTI/NSE/44821/2002). |
| Databáze: | OpenAIRE |
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