Exploring binding mechanisms in nuclear hormone receptors by Monte Carlo and x-ray-derived motions
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- dc.contributor.author Grebner, Christophca
- dc.contributor.author Lecina, Danielca
- dc.contributor.author Gil, Víctorca
- dc.contributor.author Ulander, Johanca
- dc.contributor.author Hansson, Pia K.ca
- dc.contributor.author Dellsen, Anitaca
- dc.contributor.author Tyrchan, Christianca
- dc.contributor.author Edman, Karlca
- dc.contributor.author Hogner, Anders C.ca
- dc.contributor.author Guallar i Tasies, Víctorca
- dc.date.accessioned 2018-05-16T09:18:51Z
- dc.date.available 2018-05-16T09:18:51Z
- dc.date.issued 2017
- dc.description.abstract In this study, we performed an extensive exploration of the ligand entry mechanism for members of the steroid nuclear hormone receptor family (androgen receptor, estrogen receptor α, glucocorticoid receptor, mineralocorticoid receptor, and progesterone receptor) and their endogenous ligands. The exploration revealed a shared entry path through the helix 3, 7, and 11 regions. Examination of the x-ray structures of the receptor-ligand complexes further showed two distinct folds of the helix 6-7 region, classified as "open" and "closed", which could potentially affect ligand binding. To improve sampling of the helix 6-7 loop, we incorporated motion modes based on principal component analysis of existing crystal structures of the receptors and applied them to the protein-ligand sampling. A detailed comparison with the anisotropic network model (an elastic network model) highlights the importance of flexibility in the entrance region. While the binding (interaction) energy of individual simulations can be used to score different ligands, extensive sampling further allows us to predict absolute binding free energies and analyze reaction kinetics using Markov state models and Perron-cluster cluster analysis, respectively. The predicted relative binding free energies for three ligands binding to the progesterone receptor are in very good agreement with experimental results and the Perron-cluster cluster analysis highlighted the importance of a peripheral binding site. Our analysis revealed that the flexibility of the helix 3, 7, and 11 regions represents the most important factor for ligand binding. Furthermore, the hydrophobicity of the ligand influences the transition between the peripheral and the active binding site.
- dc.format.mimetype application/pdf
- dc.identifier.citation Grebner C, Lecina D, Gil V, Ulander J, Hansson P, Dellsen A et al. Exploring Binding Mechanisms in Nuclear Hormone Receptors by Monte Carlo and X-ray-derived Motions. Biophys J. 2017 Mar; 112(6): 1147-1156. DOI: 10.1016/j.bpj.2017.02.004
- dc.identifier.doi http://dx.doi.org/10.1016/j.bpj.2017.02.004
- dc.identifier.issn 0006-3495
- dc.identifier.uri http://hdl.handle.net/10230/34645
- dc.language.iso eng
- dc.publisher Elsevierca
- dc.relation.ispartof Biophys J. 2017 Mar; 112(6): 1147-1156
- dc.rights © Elsevier This is the published version of an article http://dx.doi.org/10.1016/j.bpj.2017.02.004 that appeared in the journal Biophysical Journal. It is published in an Open Archive under an Elsevier user license. Details of this licence are available here: https://www.elsevier.com/about/our-business/policies/open-access-licenses/elsevier-user-license
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.subject.keyword Ligands
- dc.subject.keyword Protein binding
- dc.subject.keyword Mineralocorticoid receptor
- dc.subject.keyword Hormone receptor
- dc.title Exploring binding mechanisms in nuclear hormone receptors by Monte Carlo and x-ray-derived motionsca
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion