ABSTRACT
In this work, we study 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 molecular dynamics simulations of the receptor embedded in a hydrated double layer of dipalmitoyl phosphatidyl choline, a zwitterionic poly-saturated 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 and 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 shows 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 inter-dependent ways. In addition, the simulations describe an unexpected escape of histamine from the orthosteric binding site, in agreement with the experimental modest affinities and rapid off-rates of agonists.
Footnotes
LDHZ: Tecnológico de Estudios Superiores de Chicoloapan, Loma de Guadalupe., 56380 Ejido de Chicoloapan, Mexico State, MEXICO
LMMV: Computational Biology and Drug Design Research Unit. Federico Gómez Children’s Hospital of Mexico City, MEXICO
JCB: Laboratory for the Design and Development of New Drugs and Biotechnological Innovation, SEPI-ESM, Mexico City, MEXICO
Revision of the text. Renumbering and correction of figures and tables. Modification of title and update of authors' names and addresses.
