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

Detalhes bibliográficos
Autor(a) principal: Lima, Suzana Teles Cunha
Data de Publicação: 2009
Outros Autores: Nguyen, Ngoc-Ha, Togashi, Marie, Apriletti, James W., Nguyen, Phuong, Polikarpov, Igor, Scanlan, Thomas S., Baxter, John D., Webb, Paul
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UFBA
Texto Completo: http://www.repositorio.ufba.br/ri/handle/ri/6195
Resumo: Trabalho completo: acesso restrito, p. 125–131
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spelling Lima, Suzana Teles CunhaNguyen, Ngoc-HaTogashi, MarieApriletti, James W.Nguyen, PhuongPolikarpov, IgorScanlan, Thomas S.Baxter, John D.Webb, PaulLima, Suzana Teles CunhaNguyen, Ngoc-HaTogashi, MarieApriletti, James W.Nguyen, PhuongPolikarpov, IgorScanlan, Thomas S.Baxter, John D.Webb, Paul2012-06-20T20:50:14Z2009-110960-0760http://www.repositorio.ufba.br/ri/handle/ri/6195v.117, n. 4–5Trabalho completo: acesso restrito, p. 125–131Some 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.Submitted by Bruna Lessa (lessbruna@gmail.com) on 2012-06-20T20:50:14Z No. of bitstreams: 1 (82)1-s2.0-S0960076009002143-main.pdf: 710122 bytes, checksum: dcd2cf69a50373a5242a753a26a1b779 (MD5)Made available in DSpace on 2012-06-20T20:50:14Z (GMT). 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dc.title.pt_BR.fl_str_mv Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways
dc.title.alternative.pt_BR.fl_str_mv Journal of Steroid Biochemistry and Molecular Biology
title Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways
spellingShingle Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways
Lima, Suzana Teles Cunha
Thyroid hormone receptor
Triiodothyronine
Thyroxine
Selective modulator
Ligand binding
Ligand dissociation
Kinetics
Dimerization
title_short Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways
title_full Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways
title_fullStr Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways
title_full_unstemmed Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways
title_sort Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways
author Lima, Suzana Teles Cunha
author_facet Lima, Suzana Teles Cunha
Nguyen, Ngoc-Ha
Togashi, Marie
Apriletti, James W.
Nguyen, Phuong
Polikarpov, Igor
Scanlan, Thomas S.
Baxter, John D.
Webb, Paul
author_role author
author2 Nguyen, Ngoc-Ha
Togashi, Marie
Apriletti, James W.
Nguyen, Phuong
Polikarpov, Igor
Scanlan, Thomas S.
Baxter, John D.
Webb, Paul
author2_role author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Lima, Suzana Teles Cunha
Nguyen, Ngoc-Ha
Togashi, Marie
Apriletti, James W.
Nguyen, Phuong
Polikarpov, Igor
Scanlan, Thomas S.
Baxter, John D.
Webb, Paul
Lima, Suzana Teles Cunha
Nguyen, Ngoc-Ha
Togashi, Marie
Apriletti, James W.
Nguyen, Phuong
Polikarpov, Igor
Scanlan, Thomas S.
Baxter, John D.
Webb, Paul
dc.subject.por.fl_str_mv Thyroid hormone receptor
Triiodothyronine
Thyroxine
Selective modulator
Ligand binding
Ligand dissociation
Kinetics
Dimerization
topic Thyroid hormone receptor
Triiodothyronine
Thyroxine
Selective modulator
Ligand binding
Ligand dissociation
Kinetics
Dimerization
description Trabalho completo: acesso restrito, p. 125–131
publishDate 2009
dc.date.issued.fl_str_mv 2009-11
dc.date.accessioned.fl_str_mv 2012-06-20T20:50:14Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://www.repositorio.ufba.br/ri/handle/ri/6195
dc.identifier.issn.none.fl_str_mv 0960-0760
dc.identifier.number.pt_BR.fl_str_mv v.117, n. 4–5
identifier_str_mv 0960-0760
v.117, n. 4–5
url http://www.repositorio.ufba.br/ri/handle/ri/6195
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.pt_BR.fl_str_mv http://dx.doi.org/10.1016/j.jsbmb.2009.08.003
dc.source.none.fl_str_mv reponame:Repositório Institucional da UFBA
instname:Universidade Federal da Bahia (UFBA)
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institution UFBA
reponame_str Repositório Institucional da UFBA
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