Journal of Steroid Biochemistry & Molecular Biology 93 (2005) 127–137 Conformational adaptation of nuclear receptor ligand binding domains to agonists: Potential for novel approaches to ligand design Marie Togashi a , Sabine Borngraeber b , Ben Sandler b , Robert J. Fletterick b , Paul Webb a , John D. Baxter a, ∗ a Department of Medicine and the Diabetes Center, University of California, San Francisco CA 94143, USA b Departments of Biochemistry and Biophysics, University of California, San Francisco CA 94143, USA Abstract Ligands occupy the core of nuclear receptor (NR) ligand binding domains (LBDs) and modulate NR function. X-ray structures of NR LBDs reveal most NR agonists fill the enclosed pocket and promote packing of C-terminal helix 12 (H12), whereas the pockets of unliganded NR LBDs differ. Here, we review evidence that NR pockets rearrange to accommodate different agonists. Some thyroid hormone receptor (TR) ligands with 5 ′ extensions designed to perturb H12 act as antagonists, but many are agonists. One mode of adaptation is seen in a TR/thyroxine complex; the pocket expands to accommodate a 5 ′ iodine extension. Crystals of other NR LBDs reveal that the pocket can expand or contract and some agonists do not fill the pocket. A TR structure in complex with an isoform selective drug (GC-24) reveals another mode of adaptation; the LBD hydrophobic interior opens to accommodate a bulky 3 ′ benzyl extension. We suggest that placement of extensions on NR agonists will highlight unexpected areas of flexibility within LBDs that could accommodate extensions; thereby enhancing the selectivity of agonist binding to particular NRs. Finally, agonists that induce similar LBD structures differ in their activities and we discuss strategies to reveal subtle structural differences responsible for these effects. © 2005 Elsevier Ltd. All rights reserved. Keywords: Thyroid hormone receptor; Thyroid hormone 1. Introduction The nuclear receptor (NR) family of conditional tran- scription factors comprises one of the largest gene families, and includes receptors for thyroid hormone (TH), steroids, retinoids, Vitamin D, bile acids, fatty acids, cholesterol metabolites and xenobiotics [1–8]. NRs play widespread and important roles in development, metabolism and homeosta- sis and disease. Currently, about 20% of pharmaceutical pre- scriptions in the United States are for NR ligands and new selective NR agonists and antagonists with even more desir- able properties will become available in the future. For ex- ample, tested in rodents and primates, synthetic TH deriva- tives that bind selectively to the thyroid receptor  (TR) versus the TR isoform and that have selective uptake prop- ∗ Corresponding author. Tel.: +1 415 476 3166; fax: +1 415 564 5813. E-mail address: JBaxter918@aol.com (J.D. Baxter). erties reduce plasma levels of LDL cholesterol, lipoprotein Lp(a) and triglycerides more effectively than most existing treatments and also reduce body weight by as much as 7% within 1 week (with an even greater decrease in fat con- tent) without obvious ill effects [9–12]. Improved understand- ing of NR structure and function, and conformational alter- ations that accompany ligand binding, should help us identify new, and equally useful compounds that bind TRs and other NRs. Unlike the case with most classes of pharmaceuticals, mul- tiple X-ray crystal structures of NR ligand binding domains (LBDs) complexed with agonist ligands have been deter- mined [8,13]. These structures provide useful information about the nature of the hormone binding pocket, how ag- onists promote folding of the LBD activation helix (H) 12 against the body of the LBD and how to design new drugs that bind the pocket and promote or inhibit H12 folding [10]. We previously thought that TR agonists must fill the enclosed pocket and would induce a single active conformational state 0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.01.004