Molecular Dynamics Simulations Reveal Multiple Pathways Of Ligand Dissociation From Thyroid Hormone Receptors.

dc.creatorMartínez, Leandro
dc.creatorSonoda, Milton T
dc.creatorWebb, Paul
dc.creatorBaxter, John D
dc.creatorSkaf, Munir S
dc.creatorPolikarpov, Igor
dc.date2005-Sep
dc.date2015-11-27T13:02:14Z
dc.date2015-11-27T13:02:14Z
dc.date.accessioned2018-03-29T01:01:03Z
dc.date.available2018-03-29T01:01:03Z
dc.identifierBiophysical Journal. v. 89, n. 3, p. 2011-23, 2005-Sep.
dc.identifier0006-3495
dc.identifier10.1529/biophysj.105.063818
dc.identifierhttp://www.ncbi.nlm.nih.gov/pubmed/15980170
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/196322
dc.identifier15980170
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1296555
dc.descriptionNuclear 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.
dc.description89
dc.description2011-23
dc.languageeng
dc.relationBiophysical Journal
dc.relationBiophys. J.
dc.rightsaberto
dc.rights
dc.sourcePubMed
dc.subjectAlgorithms
dc.subjectAmino Acid Sequence
dc.subjectBiophysics
dc.subjectComputer Simulation
dc.subjectCrystallography, X-ray
dc.subjectHumans
dc.subjectHydrogen Bonding
dc.subjectKinetics
dc.subjectLigands
dc.subjectModels, Chemical
dc.subjectModels, Molecular
dc.subjectModels, Statistical
dc.subjectMolecular Conformation
dc.subjectMolecular Sequence Data
dc.subjectMutation
dc.subjectProtein Binding
dc.subjectProtein Conformation
dc.subjectProtein Isoforms
dc.subjectProtein Structure, Secondary
dc.subjectProtein Structure, Tertiary
dc.subjectReceptors, Thyroid Hormone
dc.subjectSequence Homology, Amino Acid
dc.subjectTemperature
dc.subjectThermodynamics
dc.subjectThyroid Hormones
dc.subjectTime Factors
dc.subjectTriiodothyronine
dc.subjectX-rays
dc.titleMolecular Dynamics Simulations Reveal Multiple Pathways Of Ligand Dissociation From Thyroid Hormone Receptors.
dc.typeArtículos de revistas


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