title: Ligand binding at the transthyretin dimer-dimer interface: structure of the transthyretin-T4Ac complex at 2.2 Angstrom resolution.
abstract: The crystal structure of the complex of human transthyretin (hTTR) with 3,3',5,5'-tetraiodothyroacetic acid (T4Ac) has been determined to 2.2 Angstrom resolution. The complex crystallizes in the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 43.46, b = 85.85, c = 65.44 Angstrom. The structure was refined to R = 17.3% and R(free) = 21.9% for reflections without any sigma-cutoff. T4Ac is bound in both the forward and the reverse mode in the two binding sites of hTTR. In the forward orientation, T4Ac binds in a position similar to that described for thyroxine (T4) in the orthorhombic hTTR-T4 complex. In this orientation, the iodine substituents of the phenolic ring are bound in the P3'/P2 halogen pockets. In the reverse orientation, which is the major binding mode of T4Ac, the ligand is bound deep in the TTR channel, with the carboxylic group bound in the P3' pocket and forming simultaneous polar interactions with the residues constituting the two hormone-binding sites. Such interactions of a thyroxine-analogue ligand bound in the reverse mode have never been observed in TTR complexes previously.
authors.affiliation: Institute of Chemistry, N. Copernicus University, Gagarina 7, 87-100 Toruń, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Neumann
authors.forename: Vivian
authors.initials: V
authors.lastname: Cody
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wojtczak
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D006219:Halogens; D006801:Humans; D007455:Iodine / Q000737:chemistry; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D008968:Molecular Conformation; D019800:Phenol / Q000737:chemistry; D011228:Prealbumin / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats; D013974:Thyroxine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D006219:Halogens; D008024:Ligands; D046911:Macromolecular Substances; D011228:Prealbumin; D019800:Phenol; D007455:Iodine; C011126:tetraiodothyroacetic acid; D013974:Thyroxine