Mechanisms and Modulation of the Thyroid Hormone Receptor

Our research focuses on the molecular and structural biology of the thyroid hormone receptor (TR) and mechanisms whereby the receptor can be modulated. Dr. Paul Webb is heavily involved as a collaborator and co-investigator in most of this work.

One effort is the elucidation of structures of the TR in collaboration with Dr. Robert Fletterick's group. We were the first group to obtain the structure of a liganded nuclear receptor. This structure was a complete surprise in that it revealed that the ligand was buried in the receptor's interior. This observation immediately suggested mechanisms for how the ligand binds, how antagonists work and how ligand binding transmits information to the receptor to mediate post-binding actions of receptors. Since then, we have determined a number of additional structures of native and mutated TR ligand binding domains. These structures have revealed: mechanisms for ligand selectivity in binding to the 2 TR isoforms (TRa and TRß) that has been useful for developing TRE-selective compounds now in human clinical trials (see below); how the receptor interacts with coactivators; mechanisms for the syndrome of resistance to thyroid hormone; and the identification of many unexpected conformations that the receptor may adopt to accommodate various ligands that, in addition, has been useful for pharmaceutical design.

A major effort is underway to use the X-ray crystal structures to direct placement of mutations that provide more information about receptor function. Surface-scanning mutagenesis allowed us to first define the structure of the coactivator binding surface and know the mechanism of how ligand binding generates the surface. We later learned that the detailed mechanisms for binding of various coactivators differ, thereby, providing mechanisms for coactivator specificity. We learned the structure of the corepressor binding surface and mechanisms whereby the corepressor could displace helix 12 of the ligand binding domain. We defined the surfaces that form homodimers with other TRs and heterodimers with the retinoid X-receptors (RXRs) and made the unexpected discovery that ligand binding promotes partial rearrangement of the dimer/heterodimer surface. We also have found that the RXR ligand binding domain must swivel with respect to its DNA binding domain to form heterodimers on certain DNA elements.

The structural data has been a stimulus to design unique ligands interacting through the TR in collaboration with Dr. Thomas Scanlan's group and other scientists. We designed the first TR antagonists that we hope some day will be used to diminish features of hyperthyroidism rapidly, unlike current therapies which usually require weeks to take effect. We have designed TRß and tissue uptake selective compounds that lower cholesterol in rodents and monkeys by promoting lowering of low density lipoprotein (LDL) cholesterol and steps in reverse cholesterol transport and also promote fat loss without muscle or bone loss or effects on the heart. We are determining mechanisms for the selectivity and the means to tailor these compounds to have even more selectivity. One of these compounds is now in human clinical trials.

Selected References

Grover, GJ, Mellström K, Ye L, Malm J, Li Y-L, Bladh L-G, Sleph PG, Smith MA, George R, Vennström B, Mookhtiar K, Horvath R, Speelman J, Egan J, Baxter JD. Selective thyroid hormone receptor- b activation: A strategy for reduction of weight, cholesterol, and Lp(a) with reduced cardiovascular liability. Proc. Natl. Acad Sci.USA. 100:10067-72 (2003).

Meng X, Webb P, Yang YF, Shuen M, Yousef AF, Baxter JD, Mymryk JS, Walfish PG. E1A and a nuclear receptor corepressor splice variant (N-CoRI) are thyroid hormone receptor coactivators that bind in the corepressor mode. Proc Natl Acad Sci U S A. 102:6267-72 (2005).