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Abstract
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.
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1 INSERM/Université d’Evry-Val d’Essonne/Université Paris-Saclay, UMR-S U1204, Structure et Activité de Biomolécules Normales et Pathologiques, Evry, France; INSERM U894, Centre de Psychiatrie et Neurosciences, Laboratoire de Neurobiologie et Pharmacologie Moléculaire, Paris, France (GRID:grid.417896.5) (ISNI:0000 0004 0638 6979); Tecnológico de Estudios Superiores del Oriente del Estado de México, Área de Estudios de Posgrado e Investigación, Los Reyes Acaquilpan, Mexico (GRID:grid.417896.5)
2 Federico Gómez Children’s Hospital of Mexico City, Computational Biology and Drug Design Research Unit, Mexico City, Mexico (GRID:grid.417896.5); INSERM U894, Centre de Psychiatrie et Neurosciences, Laboratoire de Neurobiologie et Pharmacologie Moléculaire, Paris, France (GRID:grid.417896.5) (ISNI:0000 0004 0638 6979)
3 INSERM U894, Centre de Psychiatrie et Neurosciences, Laboratoire de Neurobiologie et Pharmacologie Moléculaire, Paris, France (GRID:grid.417896.5) (ISNI:0000 0004 0638 6979)
4 INSERM/Université d’Evry-Val d’Essonne/Université Paris-Saclay, UMR-S U1204, Structure et Activité de Biomolécules Normales et Pathologiques, Evry, France (GRID:grid.417896.5); Escuela Superior de Medicina, Instituto Politécnico Nacional, Laboratorio de Modelado Molecular y Bioinformática, Mexico City, Mexico (GRID:grid.418275.d) (ISNI:0000 0001 2165 8782)
5 Federico Gómez Children’s Hospital of Mexico City, Computational Biology and Drug Design Research Unit, Mexico City, Mexico (GRID:grid.418275.d)
6 INSERM/Université d’Evry-Val d’Essonne/Université Paris-Saclay, UMR-S U1204, Structure et Activité de Biomolécules Normales et Pathologiques, Evry, France (GRID:grid.418275.d)
7 INSERM/Université d’Evry-Val d’Essonne/Université Paris-Saclay, UMR-S U1204, Structure et Activité de Biomolécules Normales et Pathologiques, Evry, France (GRID:grid.417896.5); INSERM U894, Centre de Psychiatrie et Neurosciences, Laboratoire de Neurobiologie et Pharmacologie Moléculaire, Paris, France (GRID:grid.417896.5) (ISNI:0000 0004 0638 6979)