title: Allosteric mechanisms of nuclear receptors: insights from computational simulations.
abstract: The traditional structural view of allostery defines this key regulatory mechanism as the ability of one conformational event (allosteric site) to initiate another in a separate location (active site). In recent years computational simulations conducted to understand how this phenomenon occurs in nuclear receptors (NRs) has gained significant traction. These results have yield insights into allosteric changes and communication mechanisms that underpin ligand binding, coactivator binding site formation, post-translational modifications, and oncogenic mutations. Moreover, substantial efforts have been made in understanding the dynamic processes involved in ligand binding and coregulator recruitment to different NR conformations in order to predict cell/tissue-selective pharmacological outcomes of drugs. They also have improved the accuracy of in silico screening protocols so that nowadays they are becoming part of optimisation protocols for novel therapeutics. Here we summarise the important contributions that computational simulations have made towards understanding the structure/function relationships of NRs and how these can be exploited for rational drug design.
authors.affiliation: Institute of Biomedicine of the University of Barcelona (IBUB), Department of Biochemistry and Molecular Biology, University of Barcelona (UB), Baldiri-Reixac 15-21, 08028 Barcelona, Spain.
authors.forename: Jonathan A G
authors.initials: JA
authors.lastname: Mackinnon
authors.affiliation: Institute of Biomedicine of the University of Barcelona (IBUB), Department of Biochemistry and Molecular Biology, University of Barcelona (UB), Baldiri-Reixac 15-21, 08028 Barcelona, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Gallastegui
authors.affiliation: Shifa Biomedical, 1 Great Valley Parkway, Suite 8, Malvern, PA 19355, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Osguthorpe
authors.affiliation: Department of Chemistry, University of Massachusetts, 701 Lederle, Graduate Research Tower, 710 North Pleasant Street, Amherst, MA 01003-9336, USA. Electronic address: athagler@gmail.com.
authors.forename: Arnold T
authors.initials: AT
authors.lastname: Hagler
authors.affiliation: Institute of Biomedicine of the University of Barcelona (IBUB), Department of Biochemistry and Molecular Biology, University of Barcelona (UB), Baldiri-Reixac 15-21, 08028 Barcelona, Spain. Electronic address: evaestebanez@ub.edu.
authors.forename: Eva
authors.initials: E
authors.lastname: Estébanez-Perpiñá
mesh_terms: D000495:Allosteric Site; D003198:Computer Simulation; D006801:Humans; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear
keywords: Allostery; Coregulators; Ligand binding; Molecular dynamic simulations; Nuclear receptors; Structural coupling