Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways
Autor(a) principal: | |
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Data de Publicação: | 2009 |
Outros Autores: | , , , , , , , |
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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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). No. of bitstreams: 1 (82)1-s2.0-S0960076009002143-main.pdf: 710122 bytes, checksum: dcd2cf69a50373a5242a753a26a1b779 (MD5) Previous issue date: 2009-11Elsevierhttp://dx.doi.org/10.1016/j.jsbmb.2009.08.003reponame:Repositório Institucional da UFBAinstname:Universidade Federal da Bahia (UFBA)instacron:UFBAThyroid hormone receptorTriiodothyronineThyroxineSelective modulatorLigand bindingLigand dissociationKineticsDimerizationDifferential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathwaysJournal of Steroid Biochemistry and Molecular Biologyinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article10000-01-01enginfo:eu-repo/semantics/openAccessORIGINAL(82)1-s2.0-S0960076009002143-main.pdf(82)1-s2.0-S0960076009002143-main.pdfapplication/pdf710122https://repositorio.ufba.br/bitstream/ri/6195/1/%2882%291-s2.0-S0960076009002143-main.pdfdcd2cf69a50373a5242a753a26a1b779MD51LICENSElicense.txtlicense.txttext/plain1762https://repositorio.ufba.br/bitstream/ri/6195/2/license.txt1b89a9a0548218172d7c829f87a0eab9MD52TEXT(82)1-s2.0-S0960076009002143-main.pdf.txt(82)1-s2.0-S0960076009002143-main.pdf.txtExtracted texttext/plain38658https://repositorio.ufba.br/bitstream/ri/6195/3/%2882%291-s2.0-S0960076009002143-main.pdf.txt102f7d4e1c23eaf8d9e245c2f26198eeMD53ri/61952022-07-05 14:03:43.273oai:repositorio.ufba.br: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Repositório InstitucionalPUBhttp://192.188.11.11:8080/oai/requestopendoar:19322022-07-05T17:03:43Repositório Institucional da UFBA - Universidade Federal da Bahia (UFBA)false |
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) instacron:UFBA |
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Universidade Federal da Bahia (UFBA) |
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UFBA |
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UFBA |
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Repositório Institucional da UFBA |
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Repositório Institucional da UFBA |
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