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

Leonardo David Herrera-Zúñiga,Luck Ballaud,Jean Michel Arrang,Liliana Marisol Moreno-Vargas,Rachid C Maroun,Diego Prada-Gracia,Patrick A Curmi,José Correa-Basurto,David Pastré

doi:10.1038/s41598-020-73483-5

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.

Highlights

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
C iproxifan[4,10,11] (CPX or FUB-359; CAS No 184025-18-1; GRAC database, guidetopharmacology.org; Supplementary Fig. S1b) is a highly potent and selective competitive H3-receptor antagonist/inverse agonist with pro-cognitive properties and a nanomolar affinity[12]
We have explored with atomistic molecular dynamics (MD) simulations many microscopic spatial and temporal properties of the classical activation and inactivation pathways of the second step of signal transduction pre-activation by the H3 receptor that are not accessible by experiment, including new undocumented interactions

Summary

Introduction

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. Threedimensional (3D) atomistic models of antagonist–receptor complexes have been used to investigate the details of ligand and drug interactions with H3R and have been successful in providing important insights regarding their binding; several groups have reported the features of the general H3R pharmacophore. This approach has been successful for investigating GPCR/ligand binding modes and is complementary to 3D receptor/ligand modeling. The features of this antagonist pharmacophore are a primary basic group, either a piperidine or pyrrolidine, which is connected by an alkyl linkage to a second group. In other instances, modeling of GPCRs only pretended to represent TM domains of receptor structures aimed at studying receptor-antagonist interactions and not their activated s tates[34]

Methods

Results

Conclusion