title: Conformational adaptation of nuclear receptor ligand binding domains to agonists: potential for novel approaches to ligand design.
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.
authors.affiliation: Department of Medicine and the Diabetes Center, University of California, San Francisco CA 94143, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Togashi
authors.forename: Sabine
authors.initials: S
authors.lastname: Borngraeber
authors.forename: Ben
authors.initials: B
authors.lastname: Sandler
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fletterick
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013974:Thyroxine / Q000737:chemistry / Q000378:metabolism
chemical_list: D000085:Acetates; D001559:Benzhydryl Compounds; C483767:GC 24 compound; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D013974:Thyroxine