1. Conformational adaptation of nuclear receptor ligand binding domains to agonists: potential for novel approaches to ligand design.
- Author
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Togashi M, Borngraeber S, Sandler B, Fletterick RJ, Webb P, and Baxter JD
- Subjects
- Acetates chemistry, Acetates metabolism, Amino Acid Sequence, Benzhydryl Compounds chemistry, Benzhydryl Compounds metabolism, Binding Sites genetics, Conserved Sequence, Crystallography, X-Ray, Drug Design, Humans, In Vitro Techniques, Ligands, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Structure, Tertiary, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Cytoplasmic and Nuclear metabolism, Receptors, Thyroid Hormone agonists, Receptors, Thyroid Hormone chemistry, Receptors, Thyroid Hormone genetics, Receptors, Thyroid Hormone metabolism, Sequence Homology, Amino Acid, Thyroxine chemistry, Thyroxine metabolism, Receptors, Cytoplasmic and Nuclear agonists, Receptors, Cytoplasmic and Nuclear chemistry
- 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 TRbeta 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.
- Published
- 2005
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