Review Allosteric mechanisms of nuclear receptors: insights from computational simulations Jonathan A.G. Mackinnon a,1 , Nerea Gallastegui a,1 , David J. Osguthorpe b , Arnold T. Hagler c,⇑ , Eva Estébanez-Perpiñá a,⇑ a 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 b Shifa Biomedical, 1 Great Valley Parkway, Suite 8, Malvern, PA 19355, USA c Department of Chemistry, University of Massachusetts, 701 Lederle, Graduate Research Tower, 710 North Pleasant Street, Amherst, MA 01003-9336, USA article info Article history: Received 19 March 2014 Received in revised form 15 May 2014 Accepted 19 May 2014 Available online 6 June 2014 Keywords: Nuclear receptors Molecular dynamic simulations Allostery Structural coupling Ligand binding Coregulators 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 com- munication mechanisms that underpin ligand binding, coactivator binding site formation, post-transla- tional 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 com- putational simulations have made towards understanding the structure/function relationships of NRs and how these can be exploited for rational drug design. Ó 2014 Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction .......................................................................................................... 76 2. Understanding NRs – their structure and function ........................................................................... 76 3. Ligand binding ........................................................................................................ 77 4. Coactivator binding pocket (AF-2) formation ................................................................................ 78 5. Beyond the LBP: alternative allosteric sites in NRs ........................................................................... 79 6. Post-translational modifications (PTMs) .................................................................................... 79 7. Screening for novel NR therapeutics ....................................................................................... 79 8. Concluding remarks .................................................................................................... 80 Acknowledgements .................................................................................................... 81 References ........................................................................................................... 81 http://dx.doi.org/10.1016/j.mce.2014.05.017 0303-7207/Ó 2014 Elsevier Ireland Ltd. All rights reserved. Abbreviations: AF-2, activation function 2; AP, alternative pocket; AR, androgen receptor; BF-3, binding function 3; DBD, DNA-binding domain; ER, estrogen receptor; GP, genomic pocket; GR, glucocorticoid receptor; H12, helix 12; HDX, hydrogen/deuterium exchange; LBD, ligand binding domain; LBP, ligand binding pocket; MD, molecular dynamics; NMR, nuclear magnetic resonance; NR, nuclear receptor; NTD, N-terminal domain; PTM, post-translational modification ; PPARc, peroxisome proliferator activated receptor c; REMD, replica exchange molecular dynamics; RMSD, root mean squared deviation; RAR, retinoic acid receptor; RXRa, retinoid X receptor a; SAXS, small angle X-ray scattering; VDR, vitamin D nuclear receptor; VDS, vitamin D membrane receptor; Wt, wild type. ⇑ Corresponding authors. Tel.: +34 4031119. E-mail addresses: athagler@gmail.com (A.T. Hagler), evaestebanez@ub.edu (E. Estébanez-Perpiñá). 1 Both authors contributed equally to this work. Molecular and Cellular Endocrinology 393 (2014) 75–82 Contents lists available at ScienceDirect Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce