Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways

Autor(es)

Cunha Lima, Suzana T. ^[1] ; Nguyen, Ngoc-Ha ^[2] ; Togashi, Marie ^[3] ; Apriletti, James W. ^[4] ; Nguyen, Phuong ^[4] ; Polikarpov, Igor ^[5] ; Scanlan, Thomas S. ^[6] ; Baxter, John D. ^[7] ; Webb, Paul ^[7]

Afiliação do(s) autor(es)

^[1] Univ Fed Bahia, Dept Gen Biol, Inst Biol, BR-40170290 Salvador, BA - Brazil

^[2] Univ Calif San Francisco, Dept Biochem & Biophys, Sch Med, San Francisco, CA 94143 - USA

^[3] Univ Brasilia, Hlth Sci Inst, BR-70919970 Brasilia, DF - Brazil

^[4] Univ Calif San Francisco, Sch Med, Ctr Diabet, San Francisco, CA 94143 - USA

^[5] Univ Sao Paulo, Phys Inst Sao Carlos, BR-13560970 Sao Carlos, SP - Brazil

^[6] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97239 - USA

^[7] Methodist Hosp, Res Inst, Houston, TX 77030 - USA

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY; v. 117, n. 4-5, p. 125-131, NOV 2009.
• Citações Web of Science: 3

Resumo

Some nuclear receptor (NR) ligands promote dissociation of radiolabeled bound hormone from the buried ligand binding cavity (LBC) more rapidly than excess unlabeled hormone itself This result was interpreted to mean that challenger ligands bind allosteric sites on the LBD to induce hormone dissociation, and recent findings indicate that ligands bind weakly to multiple sites on the LBD surface. Here we show, that a large fraction of thyroid hormone receptor (TR) ligands promote rapid dissociation (T(1/2) < 2 h) of , radiolabeled T(3) vs. T(3) (T(1/2), approximate to 5-7 h). We cannot discern relationships between this effect and ligand size, activity or affinity for TR beta. One ligand, GC-24, binds the TR LBC and (weakly) to the TR beta-LBD surface that mediates dimer/heterodimer interaction, but we cannot link this interaction to rapid T(3) dissociation. Instead, several lines of evidence suggest that the challenger ligand must interact with the buried LBC to promote rapid T(3) release. Since previous molecular dynamics simulations suggest that TR ligands leave the LBC by several routes, we propose that a subset of challenger ligands binds and stabilizes a partially unfolded intermediate state of TR that arises during T(3) release and that this effect enhances hormone dissociation. (C) 2009 Elsevier Ltd. All rights reserved. (AU)

• Processo FAPESP: 06/00182-8 - Biofísica estrutural dos receptores nucleares e proteínas relacionadas
• Beneficiário: Igor Polikarpov
• Linha de fomento: Auxílio à Pesquisa - Temático