Only Subtle Protein Conformational Adaptations Are Required For Ligand Binding To Thyroid Hormone Receptors: Simulations Using A Novel Multipoint Steered Molecular Dynamics Approach.

dc.creatorMartínez, Leandro
dc.creatorPolikarpov, Igor
dc.creatorSkaf, Munir S
dc.date2008-Aug
dc.date2015-11-27T13:13:05Z
dc.date2015-11-27T13:13:05Z
dc.date.accessioned2018-03-29T01:07:18Z
dc.date.available2018-03-29T01:07:18Z
dc.identifierThe Journal Of Physical Chemistry. B. v. 112, n. 34, p. 10741-51, 2008-Aug.
dc.identifier1520-6106
dc.identifier10.1021/jp803403c
dc.identifierhttp://www.ncbi.nlm.nih.gov/pubmed/18681473
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/197923
dc.identifier18681473
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1298156
dc.descriptionThyroid hormone receptors (TR) are hormone-dependent transcription regulators that play a major role in human health, development, and metabolic functions. The thyroid hormone resistance syndrome, diabetes, obesity, and some types of cancer are just a few examples of important diseases that are related to TR malfunctioning, particularly impaired hormone binding. Ligand binding to and dissociation from the receptor ultimately control gene transcription and, thus, detailed knowledge of binding and release mechanisms are fundamental for the comprehension of the receptor's biological function and development of pharmaceuticals. In this work, we present the first computational study of ligand entry into the ligand binding domain (LBD) of a nuclear receptor. We report molecular dynamics simulations of ligand binding to TRs using a generalization of the steered molecular dynamics technique designed to perform single-molecule pulling simulations along arbitrarily nonlinear driving pathways. We show that only gentle protein movements and conformational adaptations are required for ligand entry into the LBDs and that the magnitude of the forces applied to assist ligand binding are of the order of the forces involved in ligand dissociation. Our simulations suggest an alternative view for the mechanisms ligand binding and dissociation of ligands from nuclear receptors in which ligands can simply diffuse through the protein surface to reach proper positioning within the binding pocket. The proposed picture indicates that the large-amplitude protein motions suggested by the apo- and holo-RXRalpha crystallographic structures are not required, reconciling conformational changes of LBDs required for ligand entry with other nuclear receptors apo-structures that resemble the ligand-bound LBDs.
dc.description112
dc.description10741-51
dc.languageeng
dc.relationThe Journal Of Physical Chemistry. B
dc.relationJ Phys Chem B
dc.rightsfechado
dc.rights
dc.sourcePubMed
dc.subjectAlgorithms
dc.subjectBinding Sites
dc.subjectComputer Simulation
dc.subjectHumans
dc.subjectLigands
dc.subjectModels, Molecular
dc.subjectMolecular Structure
dc.subjectProtein Conformation
dc.subjectProtein Structure, Tertiary
dc.subjectReceptors, Thyroid Hormone
dc.subjectThyroid Hormone Receptors Alpha
dc.subjectThyroid Hormone Receptors Beta
dc.subjectThyroid Hormones
dc.titleOnly Subtle Protein Conformational Adaptations Are Required For Ligand Binding To Thyroid Hormone Receptors: Simulations Using A Novel Multipoint Steered Molecular Dynamics Approach.
dc.typeArtículos de revistas


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