1Y1D

Crystal structure of transthyretin in complex with iododiflunisal

Summary for 1Y1D

• Entry DOI: 10.2210/pdb1y1d/pdb
• Descriptor: Transthyretin, 2',4'-DIFLUORO-4-HYDROXY-5-IODO-1,1'-BIPHENYL-3-CARBOXYLIC ACID (3 entities in total)
• Functional Keywords: transthyretin, amyloid, iododiflunisal, transport protein
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 28306.91

Authors

Gales, L.,Macedo-Ribeiro, S.,Arsequell, G.,Valencia, G.,Saraiva, M.J.,Damas, A.M. (deposition date: 2004-11-18, release date: 2005-07-26, Last modification date: 2023-08-23)

Primary citation

Gales, L.,Macedo-Ribeiro, S.,Arsequell, G.,Valencia, G.,Saraiva, M.J.,Damas, A.M.
Human transthyretin in complex with iododiflunisal: structural features associated with a potent amyloid inhibitor.
Biochem.J., 388:615-621, 2005

PubMed Abstract: 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 N(zeta) 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.

PubMed: 15689188
DOI: 10.1042/BJ20042035

Experimental method

X-RAY DIFFRACTION (1.7 Å)