Identification of a novel ligand binding motif in the transthyretin channel

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 1; pp. 100 - 110
• Main Authors: Lima, Luis Mauricio T.R., Silva, Vivian de Almeida, Palmieri, Leonardo de Castro, Oliveira, Maria Clara B.R., Foguel, Débora, Polikarpov, Igor
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 2010; Elsevier
• Subjects: Amyloid; Amyloid - drug effects; Amyloidosis - drug therapy; Anilino Naphthalenesulfonates - chemistry; Anilino Naphthalenesulfonates - pharmacology; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Hormone binding site; Humans; Ligands; Medical sciences; Miscellaneous; Models, Molecular; Naphthalenesulfonate; Naphthalenesulfonates - chemistry; Naphthalenesulfonates - pharmacology; Pharmacology. Drug treatments; Prealbumin - chemistry; Prealbumin - metabolism; Protein Binding; Protein Conformation; Transthyretin; T4; 1,5-AmNS; TTR; 1,8-ANS; Transthyretin; Amyloid; Hormone binding site; Naphthalenesulfonate; Ligand binding; Molecular structure; Aniline derivatives; Binding site; Serum protein; X ray diffraction; Modeling; Diclofenac; Binding protein; Arylacetic acid derivatives; Thyroxine binding prealbumin; Binding isotherm; Molecular model; Aromatic amine; Crystalline structure
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.11.025

The design of therapeutic compounds targeting transthyretin (TTR) is challenging due to the low specificity of interaction in the hormone binding site. Such feature is highlighted by the interactions of TTR with diclofenac, a compound with high affinity for TTR, in two dissimilar modes, as evidenced by crystal structure of the complex. We report here structural analysis of the interactions of TTR with two small molecules, 1-amino-5-naphthalene sulfonate (1,5-AmNS) and 1-anilino-8-naphthalene sulfonate (1,8-ANS). Crystal structure of TTR:1,8-ANS complex reveals a peculiar interaction, through the stacking of the naphthalene ring between the side-chain of Lys15 and Leu17. The sulfonate moiety provides additional interaction with Lys15′ and a water-mediated hydrogen bond with Thr119′. The uniqueness of this mode of ligand recognition is corroborated by the crystal structure of TTR in complex with the weak analogue 1,5-AmNS, the binding of which is driven mainly by hydrophobic partition and one electrostatic interaction between the sulfonate group and the Lys15. The ligand binding motif unraveled by 1,8-ANS may open new possibilities to treat TTR amyloid diseases by the elucidation of novel candidates for a more specific pharmacophoric pattern.