TY - JOUR
T1 - X-ray crystallographic and functional studies of thyroid hormone receptor
AU - Ribeiro, Ralff C.J.
AU - Apriletti, James W.
AU - Wagner, Richard L.
AU - Feng, Weijun
AU - Kushner, Peter J.
AU - Nilsson, Stefan
AU - Scanlan, Thomas S.
AU - West, Brian L.
AU - Fletterick, Robert J.
AU - Baxter, John D.
PY - 1998/1/1
Y1 - 1998/1/1
N2 - We have solved several X-ray crystallographic structures of TR ligand- binding domains (LBDs), including the rat (r) TRα and the human (h) TRβ bound to diverse ligands. The TR-LBD folding, comprised mostly of α-helices, is likely to be general for the superfamily. The ligand, buried in the receptor, forms part of its hydrophobic core. Tight fitting of ligand into the receptor explains its high affinity for the TR, although the structure suggests that ligands with even higher affinities might be generated. The kinetics of 3,5,3'-triiodo-L-thyronine (T3) and 3,5,3',5'-tetraiodo-L- thyronine (T4) binding suggest that folding around the ligand, rather than receptor opening, is rate-limiting for high affinity binding. TRβ mutations in patients with resistance to T3 cluster around the ligand; these different locations could differentially affect on other receptor functions and explain the syndrome's clinical diversity. Guided by the structure, mutations have been placed on the TR surface to define interactions with other proteins. They suggest that a similar surface in the LBD is utilized for homo-or heterodimerization on direct repeats and inverted palindromes but not on palindromes. Coactivator proteins that mediate TR transcriptional activation bind to a small surface comprised of residues on four helices with a well- defined hydrophobic cleft, which may be a target for pharmaceuticals. The coactivator-binding surface appears to form upon ligand-binding by the folding of helix 12 into the scaffold formed by helices 3, 4 and 5. The analysis of most currently used antagonists suggest that although they probably fit into the ligand-binding pocket, they possess a group that may alter proper folding of the receptor, with disruption of the coactivator- binding surface (the 'extension model').
AB - We have solved several X-ray crystallographic structures of TR ligand- binding domains (LBDs), including the rat (r) TRα and the human (h) TRβ bound to diverse ligands. The TR-LBD folding, comprised mostly of α-helices, is likely to be general for the superfamily. The ligand, buried in the receptor, forms part of its hydrophobic core. Tight fitting of ligand into the receptor explains its high affinity for the TR, although the structure suggests that ligands with even higher affinities might be generated. The kinetics of 3,5,3'-triiodo-L-thyronine (T3) and 3,5,3',5'-tetraiodo-L- thyronine (T4) binding suggest that folding around the ligand, rather than receptor opening, is rate-limiting for high affinity binding. TRβ mutations in patients with resistance to T3 cluster around the ligand; these different locations could differentially affect on other receptor functions and explain the syndrome's clinical diversity. Guided by the structure, mutations have been placed on the TR surface to define interactions with other proteins. They suggest that a similar surface in the LBD is utilized for homo-or heterodimerization on direct repeats and inverted palindromes but not on palindromes. Coactivator proteins that mediate TR transcriptional activation bind to a small surface comprised of residues on four helices with a well- defined hydrophobic cleft, which may be a target for pharmaceuticals. The coactivator-binding surface appears to form upon ligand-binding by the folding of helix 12 into the scaffold formed by helices 3, 4 and 5. The analysis of most currently used antagonists suggest that although they probably fit into the ligand-binding pocket, they possess a group that may alter proper folding of the receptor, with disruption of the coactivator- binding surface (the 'extension model').
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U2 - 10.1016/S0960-0760(98)00029-6
DO - 10.1016/S0960-0760(98)00029-6
M3 - Article
C2 - 9699866
AN - SCOPUS:0032052809
VL - 65
SP - 133
EP - 141
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
SN - 0960-0760
IS - 1-6
ER -