Molecular dynamics of the histamine H3 membrane receptor reveals different mechanisms of GPCR signal transduction.

Autor: Herrera-Zúñiga LD; UMR-S U1204, Structure et Activité de Biomolécules Normales et Pathologiques, INSERM/Université d'Evry-Val d'Essonne/Université Paris-Saclay, 91000, Evry, France.; Laboratoire de Neurobiologie et Pharmacologie Moléculaire, INSERM U894, Centre de Psychiatrie et Neurosciences, 75014, Paris, France.; Área de Estudios de Posgrado e Investigación, Tecnológico de Estudios Superiores del Oriente del Estado de México, Los Reyes Acaquilpan, Mexico., Moreno-Vargas LM; Computational Biology and Drug Design Research Unit, Federico Gómez Children's Hospital of Mexico City, Mexico City, Mexico.; Laboratoire de Neurobiologie et Pharmacologie Moléculaire, INSERM U894, Centre de Psychiatrie et Neurosciences, 75014, Paris, France., Ballaud L; Laboratoire de Neurobiologie et Pharmacologie Moléculaire, INSERM U894, Centre de Psychiatrie et Neurosciences, 75014, Paris, France., Correa-Basurto J; UMR-S U1204, Structure et Activité de Biomolécules Normales et Pathologiques, INSERM/Université d'Evry-Val d'Essonne/Université Paris-Saclay, 91000, Evry, France.; Laboratorio de Modelado Molecular y Bioinformática, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico., Prada-Gracia D; Computational Biology and Drug Design Research Unit, Federico Gómez Children's Hospital of Mexico City, Mexico City, Mexico., Pastré D; UMR-S U1204, Structure et Activité de Biomolécules Normales et Pathologiques, INSERM/Université d'Evry-Val d'Essonne/Université Paris-Saclay, 91000, Evry, France., Curmi PA; UMR-S U1204, Structure et Activité de Biomolécules Normales et Pathologiques, INSERM/Université d'Evry-Val d'Essonne/Université Paris-Saclay, 91000, Evry, France., Arrang JM; Laboratoire de Neurobiologie et Pharmacologie Moléculaire, INSERM U894, Centre de Psychiatrie et Neurosciences, 75014, Paris, France., Maroun RC; UMR-S U1204, Structure et Activité de Biomolécules Normales et Pathologiques, INSERM/Université d'Evry-Val d'Essonne/Université Paris-Saclay, 91000, Evry, France. charbel.maroun@inserm.fr.; Laboratoire de Neurobiologie et Pharmacologie Moléculaire, INSERM U894, Centre de Psychiatrie et Neurosciences, 75014, Paris, France. charbel.maroun@inserm.fr.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2020 Oct 09; Vol. 10 (1), pp. 16889. Date of Electronic Publication: 2020 Oct 09.
DOI: 10.1038/s41598-020-73483-5
Abstrakt: In 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.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje