Molecular dynamics simulations reveal multiple pathways of ligand dissociation from thyroid hormone receptors

dc.creatorMartinez, L
dc.creatorSonoda, MT
dc.creatorWebb, P
dc.creatorBaxter, JD
dc.creatorSkaf, MS
dc.creatorPolikarpov, I
dc.date2005
dc.dateSEP
dc.date2014-11-17T01:50:57Z
dc.date2015-11-26T16:35:09Z
dc.date2014-11-17T01:50:57Z
dc.date2015-11-26T16:35:09Z
dc.date.accessioned2018-03-28T23:17:33Z
dc.date.available2018-03-28T23:17:33Z
dc.identifierBiophysical Journal. Biophysical Society, v. 89, n. 3, n. 2011, n. 2023, 2005.
dc.identifier0006-3495
dc.identifierWOS:000231502800057
dc.identifier10.1529/biophysj.105.063818
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/57770
dc.identifierhttp://www.repositorio.unicamp.br/handle/REPOSIP/57770
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/57770
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1271422
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 TR alpha 1 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 TR beta-selective ligand GC24 from TR beta; the TR agonist IH5 from the alpha- and beta-TR forms; and Triac from two natural human TR beta 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.description3
dc.description2011
dc.description2023
dc.languageen
dc.publisherBiophysical Society
dc.publisherBethesda
dc.publisherEUA
dc.relationBiophysical Journal
dc.relationBiophys. J.
dc.rightsaberto
dc.sourceWeb of Science
dc.subjectTime-dependent Hartree
dc.subjectBinding Domain
dc.subjectEstrogen-receptor
dc.subjectCrystal-structure
dc.subjectRetinoic Acid
dc.subjectNuclear Receptors
dc.subject3-dimensional Structures
dc.subjectConformational-changes
dc.subjectForce-field
dc.subjectMyoglobin
dc.titleMolecular dynamics simulations reveal multiple pathways of ligand dissociation from thyroid hormone receptors
dc.typeArtículos de revistas


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