Author:
Herrera-Zúñiga Leonardo David,Moreno-Vargas Liliana Marisol,Ballaud Luck,Correa-Basurto José,Prada-Gracia Diego,Pastré David,Curmi Patrick A.,Arrang Jean Michel,Maroun Rachid C.
Abstract
AbstractIn this work, we studied the mechanisms of classical activation and inactivation of signal transduction by the histamine H3 receptor, a 7-helix transmembrane bundle G-Protein Coupled Receptor through long-time-scale atomistic molecular dynamics simulations of the receptor embedded in a hydrated double layer of dipalmitoyl phosphatidyl choline, a zwitterionic polysaturated ordered lipid. Three systems were prepared: the apo receptor, representing the constitutively active receptor; and two holo-receptors—the receptor coupled to the antagonist/inverse agonist ciproxifan, representing the inactive state of the receptor, and the receptor coupled to the endogenous agonist histamine and representing the active state of the receptor. An extensive analysis of the simulation showed that the three states of H3R present significant structural and dynamical differences as well as a complex behavior given that the measured properties interact in multiple and interdependent ways. In addition, the simulations described an unexpected escape of histamine from the orthosteric binding site, in agreement with the experimental modest affinities and rapid off-rates of agonists.
Funder
ECOS Nord-ANUIES Mexique
Institut National de la Santé et de la Recherche Médicale
Université d’Evry-Val d’Essonne/Université Paris Saclay
Institut de Recherches Servier
Publisher
Springer Science and Business Media LLC
Cited by
4 articles.
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