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A complex view of GPCR signal transduction: Molecular dynamics of the histamine H3 membrane receptor

Résumé : 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.
Abstract : 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.
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Preprints, Working Papers, ...
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https://hal-univ-evry.archives-ouvertes.fr/hal-02968906
Contributor : Olek Maciejak <>
Submitted on : Friday, October 16, 2020 - 11:04:06 AM
Last modification on : Thursday, October 22, 2020 - 9:50:37 AM

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L. Herrera-Zúñiga, L. Moreno-Vargas, L. Ballaud, J. Correa-Basurto, D. Prada-Gracia, et al.. A complex view of GPCR signal transduction: Molecular dynamics of the histamine H3 membrane receptor. 2020. ⟨hal-02968906⟩

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