A dynamic view of molecular switch behavior at serotonin receptors: implications for functional selectivity

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• dc.contributor.author Martí Solano, Mariaca
• dc.contributor.author Sanz, Ferranca
• dc.contributor.author Pastor Maeso, Manuelca
• dc.contributor.author Selent, Janaca
• dc.date.accessioned 2015-05-25T09:06:49Z
• dc.date.available 2015-05-25T09:06:49Z
• dc.date.issued 2014ca
• dc.description.abstract Functional selectivity is a property of G protein-coupled receptors that allows them to preferentially couple to particular signaling partners upon binding of biased agonists. Publication of the X-ray crystal structure of serotonergic 5-HT1B and 5-HT2B receptors in complex with ergotamine, a drug capable of activating G protein coupling and β-arrestin signaling at the 5-HT1B receptor but clearly favoring β-arrestin over G protein coupling at the 5-HT2B subtype, has recently provided structural insight into this phenomenon. In particular, these structures highlight the importance of specific residues, also called micro-switches, for differential receptor activation. In our work, we apply classical molecular dynamics simulations and enhanced sampling approaches to analyze the behavior of these micro-switches and their impact on the stabilization of particular receptor conformational states. Our analysis shows that differences in the conformational freedom of helix 6 between both receptors could explain their different G protein-coupling capacity. In particular, as compared to the 5-HT1B receptor, helix 6 movement in the 5-HT2B receptor can be constrained by two different mechanisms. On the one hand, an anchoring effect of ergotamine, which shows an increased capacity to interact with the extracellular part of helices 5 and 6 and stabilize them, hinders activation of a hydrophobic connector region at the center of the receptor. On the other hand, this connector region in an inactive conformation is further stabilized by unconserved contacts extending to the intracellular part of the 5-HT2B receptor, which hamper opening of the G protein binding site. This work highlights the importance of considering receptor capacity to adopt different conformational states from a dynamic perspective in order to underpin the structural basis of functional selectivity.en
• dc.description.sponsorship This work was funded by the Ministerio de Educación y Ciencia, grant number SAF2009-13609-C04-04, and La MARATÓ de TV3 Foundation, grant number 091010. MM-S is supported by a doctoral fellowship from the University and Research Secretariat of the Catalan Government and the European Social Fund (2013FI_B 00143). JS acknowledges support from the Instituto de Salud Carlos III FEDER (CP12/03139) and the GLISTEN European Research Networken
• dc.format.mimetype application/pdfca
• dc.identifier.citation Martí-Solano M, Sanz F, Pastor M, Selent J. A dynamic view of molecular switch behavior at serotonin receptors: implications for functional selectivity. PLoS ONE. 2014;9(10):e409312. DOI: 10.1371/journal.pone.0109312ca
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0109312
• dc.identifier.issn 1932-6203ca
• dc.identifier.uri http://hdl.handle.net/10230/23645
• dc.language.iso engca
• dc.publisher Public Library of Science (PLoS)ca
• dc.relation.ispartof PLoS ONE. 2014;9(10):e409312
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2009-13609
• dc.rights © 2014 Martí-Solano et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are crediteden
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.other Serotonina -- Receptorsca
• dc.subject.other Proteïnesca
• dc.title A dynamic view of molecular switch behavior at serotonin receptors: implications for functional selectivityen
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca