2roy
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TRANSTHYRETIN (ALSO CALLED PREALBUMIN) COMPLEX WITH 3',5'-DINITRO-N-ACETYL-L-THYRONINE
OverviewOverview
The molecular structures of two human transthyretin (hTTR, prealbumin), complexes, co-crystallized with thyroxine, (3,5,3',5'-tetraiodo-L-thyronine; T(4)), and with, 3',5'-dinitro-N-acetyl-LL-thyronine (DNNAT), were determined by X-ray, diffraction methods. Crystals of both structures are orthorhombic, space, group P2(1)2(1)2, and have two independent monomers in the asymmetric unit, of the crystal lattice. These structures have been refined to 17.0% for, 8-2.0 A resolution data for the T(4) complex (I), and to R = 18.4% for, 8-2.2 A resolution data for the DNNAT structure (II). This report provides, a detailed description of T(4) binding to wild-type hTTR at 2.0 A, resolution, as well as DNNAT. In both structures, the two independent, hormone-binding sites of the TTR tetramer are occupied by ligand. A 50%, statistical disorder model was applied to account for the crystallographic, twofold symmetry along the binding channel and the lack of such symmetry, for the ligands. Results for the co-crystallized T(4) complex show that, T(4) binds deep in the hormone-binding channel and displaces the bound, water previously reported for T(4) soaked into a native transthyretin, crystal [Blake & Oatley (1977). Nature (London), 268, 115-120]. DNNAT also, binds deeper in the channel toward the tetramer center than T(4) with the, nitro groups occupying the symmetrical innermost halogen pockets. The, N-acetyl moiety does not form polar contacts with the protein side chains, as it is oriented toward the center of the channel. The weak binding, affinity of DNNAT results from the loss of hydrophobic interactions with, the halogen binding pockets as observed in T(4) binding. These data, suggest that the halogen-binding sites toward the tetramer center are of, primary importance as they are occupied by analogues with weak affinity to, TTR, and are therefore selected over the other halogen sites which, contribute more strongly to the overall binding affinity.
DiseaseDisease
Known diseases associated with this structure: Amyloid neuropathy, familial, several allelic types OMIM:[176300], Amyloidosis, senile systemic OMIM:[176300], Carpal tunnel syndrome, familial OMIM:[176300], Dystransthyretinemic hyperthyroxinemia OMIM:[176300]
About this StructureAbout this Structure
2ROY is a Single protein structure of sequence from Homo sapiens with P28 as ligand. This structure superseeds the now removed PDB entry 1ROY. Known structural/functional Sites: and . Full crystallographic information is available from OCA.
ReferenceReference
Structures of human transthyretin complexed with thyroxine at 2.0 A resolution and 3',5'-dinitro-N-acetyl-L-thyronine at 2.2 A resolution., Wojtczak A, Cody V, Luft JR, Pangborn W, Acta Crystallogr D Biol Crystallogr. 1996 Jul 1;52(Pt 4):758-65. PMID:15299640
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