Differential effects of TR ligands on hormone dissociation rates

Evidence for multiple ligand entry/exit pathways

Suzana T. Cunha Lima, Ngoc Ha Nguyen, Marie Togashi, James W. Apriletti, Phuong Nguyen, Igor Polikarpov, Thomas (Tom) Scanlan, John D. Baxter, Paul Webb

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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 (T1/2 <2 h) of radiolabeled T3 vs. T3 (T1/2 ≈ 5-7 h). We cannot discern relationships between this effect and ligand size, activity or affinity for TRβ. One ligand, GC-24, binds the TR LBC and (weakly) to the TRβ-LBD surface that mediates dimer/heterodimer interaction, but we cannot link this interaction to rapid T3 dissociation. Instead, several lines of evidence suggest that the challenger ligand must interact with the buried LBC to promote rapid T3 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 T3 release and that this effect enhances hormone dissociation.

Original languageEnglish (US)
Pages (from-to)125-131
Number of pages7
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume117
Issue number4-5
DOIs
StatePublished - Nov 2009

Fingerprint

Thyroid Hormone Receptors
Hormones
Ligands
Allosteric Site
Molecular Dynamics Simulation
Cytoplasmic and Nuclear Receptors
Dimers
Molecular dynamics

Keywords

  • Dimerization
  • Kinetics
  • Ligand binding
  • Ligand dissociation
  • Selective modulator
  • Thyroid hormone receptor
  • Thyroxine
  • Triiodothyronine

ASJC Scopus subject areas

  • Molecular Medicine
  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Cell Biology
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Differential effects of TR ligands on hormone dissociation rates : Evidence for multiple ligand entry/exit pathways. / Cunha Lima, Suzana T.; Nguyen, Ngoc Ha; Togashi, Marie; Apriletti, James W.; Nguyen, Phuong; Polikarpov, Igor; Scanlan, Thomas (Tom); Baxter, John D.; Webb, Paul.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 117, No. 4-5, 11.2009, p. 125-131.

Research output: Contribution to journalArticle

Cunha Lima, Suzana T. ; Nguyen, Ngoc Ha ; Togashi, Marie ; Apriletti, James W. ; Nguyen, Phuong ; Polikarpov, Igor ; Scanlan, Thomas (Tom) ; Baxter, John D. ; Webb, Paul. / Differential effects of TR ligands on hormone dissociation rates : Evidence for multiple ligand entry/exit pathways. In: Journal of Steroid Biochemistry and Molecular Biology. 2009 ; Vol. 117, No. 4-5. pp. 125-131.
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