X-RAY CRYSTALLOGRAPHIC AND FUNCTIONAL-STUDIES OF THYROID-HORMONE RECEPTOR

We have solved several X-ray crystallographic structures of TR ligand- binding domains (LBDs), including the rat (r) TR alpha and the human ( h) TR beta bound to diverse ligands. The TR-LBD folding, comprised mos tly of a-helices, is Likely to be general for the superfamily. The lig and, buried in the receptor, forms part of its hydrophobic core. Tight fitting of ligand into the receptor explains its high affinity for th e TR, although the structure suggests that ligands with even higher af finities might be generated. The kinetics of 3,5,3'-triiodo-L-thyronin e (T-3) and 3,5,3',5'-tetraiodo-L-thyronine (T-4) binding suggest that folding around the ligand, rather than receptor opening, is rate-limi ting for high affinity binding. TR beta mutations in patients with res istance to T-3 cluster around the Ligand; these different locations co uld 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 prote ins. They suggest that a similar surface in the LED is utilized for ho me-or heterodimerization on direct repeats and inverted palindromes bu t not on palindromes. Coactivator proteins that mediate TR transcripti onal activation bind to a small surface comprised of residues on four helices with a well-defined hydrophobic cleft, which may be a target f or pharmaceuticals. The coactivator-binding surface appears to form up on 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 pocke t, they possess a group that may alter proper folding of the receptor, with disruption of the coactivator-binding surface (the 'extension mo del'). (C) 1998 Published by Elsevier Science Ltd. All rights reserved .