Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/244241
Type: Artigo de periódico
Title: Conformational Diversity Of The Helix 12 Of The Ligand Binding Domain Of Ppar Gamma And Functional Implications
Author: Batista
Mariana R. B.; Martinez
Leandro
Abstract: Nuclear hormone receptors (NR) are transcription factors that activate gene expression in response to ligands. Structural and functional studies Of the ligand binding domains (LBD) of NRs revealed that the dynamics Of Their C-terminal helix (H12) is fundamental for NR activity. 1112 is rigid and facilitates binding of coactivator proteins in the agonist-bound LBD. In the absence of ligand, H12 exhibits increased flexibility. To provide a comprehensive picture of the H12 conformational equilibrium, extensive molecular dynamics simulations of the LBD of the PPAR gamma receptor in the presence or absence of ligand, and of coactivators and corepressor peptides, were performed. Free-energy profiles Of the conformational variability of the H12 were obtained from more than four microseconds of simulations using adaptive biasing-force calculations. Our results demonstrate that, without ligand, multiple conformations of the H12 are accessble, including agonist-like conformations. We also confirm that extended H12 conformations are not accessible at ordinary temperatures.. Ligand binding stabilizes the agonist 1112 conformation relative to other structures, promoting a conformational selection. Similar effects are observed with coactivator association. The presence of corepressor peptides stabilizes conformations not allowed in the ligand-free, Rosiglitazone-bound or coactivator-bound LBDs. Corepressor binding, therefore, induces a conformational transition in the protein. Nevertheless,, initial stages of corepressor dissociation could be induced by the ligand as it stabilizes the H12 in agonist form. Therefore, the present results provide a comprehensive picture of the H12 motions and their functional implications, with molecular resolution.
Subject: Molecular-dynamics Simulations
Thyroid-hormone Receptors
Crystal-structure
Retinoic Acid
Initial Configurations
Estrogen-receptor
Nuclear Receptors
Activation
Mechanism
Protein
Country: WASHINGTON
Editor: AMER CHEMICAL SOC
Citation: Conformational Diversity Of The Helix 12 Of The Ligand Binding Domain Of Ppar Gamma And Functional Implications. Amer Chemical Soc, v. 119, p. 15418-15429 DEC-2015.
Rights: fechado
Identifier DOI: 10.1021/acs.jpcb.5b09824
Address: http://www.cheric.org/research/tech/periodicals/view.php?seq=1389315
Date Issue: 2015
Appears in Collections:Unicamp - Artigos e Outros Documentos

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.