Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/196322
Type: Artigo de periódico
Title: Molecular Dynamics Simulations Reveal Multiple Pathways Of Ligand Dissociation From Thyroid Hormone Receptors.
Author: Martínez, Leandro
Sonoda, Milton T
Webb, Paul
Baxter, John D
Skaf, Munir S
Polikarpov, Igor
Abstract: Nuclear receptor (NR) ligands occupy a pocket that lies within the core of the NR ligand-binding domain (LBD), and most NR LBDs lack obvious entry/exit routes upon the protein surface. Thus, significant NR conformational rearrangements must accompany ligand binding and release. The precise nature of these processes, however, remains poorly understood. Here, we utilize locally enhanced sampling (LES) molecular dynamics computer simulations to predict molecular motions of x-ray structures of thyroid hormone receptor (TR) LBDs and determine events that permit ligand escape. We find that the natural ligand 3,5,3'-triiodo-L-thyronine (T(3)) dissociates from the TRalpha1 LBD along three competing pathways generated through i), opening of helix (H) 12; ii), separation of H8 and H11 and the Omega-loop between H2 and H3; and iii), opening of H2 and H3, and the intervening beta-strand. Similar pathways are involved in dissociation of T(3) and the TRbeta-selective ligand GC24 from TRbeta; the TR agonist IH5 from the alpha- and beta-TR forms; and Triac from two natural human TRbeta mutants, A317T and A234T, but are detected with different frequencies in simulations performed with the different structures. Path I was previously suggested to represent a major pathway for NR ligand dissociation. We propose here that Paths II and III are also likely ligand escape routes for TRs and other NRs. We also propose that different escape paths are preferred in different situations, implying that it will be possible to design NR ligands that only associate stably with their cognate receptors in specific cellular contexts.
Subject: Algorithms
Amino Acid Sequence
Biophysics
Computer Simulation
Crystallography, X-ray
Humans
Hydrogen Bonding
Kinetics
Ligands
Models, Chemical
Models, Molecular
Models, Statistical
Molecular Conformation
Molecular Sequence Data
Mutation
Protein Binding
Protein Conformation
Protein Isoforms
Protein Structure, Secondary
Protein Structure, Tertiary
Receptors, Thyroid Hormone
Sequence Homology, Amino Acid
Temperature
Thermodynamics
Thyroid Hormones
Time Factors
Triiodothyronine
X-rays
Rights: aberto
Identifier DOI: 10.1529/biophysj.105.063818
Address: http://www.ncbi.nlm.nih.gov/pubmed/15980170
Date Issue: 2005
Appears in Collections:Unicamp - Artigos e Outros Documentos

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