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

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Leonardo David Herrera-Zúñiga ◽  
Liliana Marisol Moreno-Vargas ◽  
Luck Ballaud ◽  
José Correa-Basurto ◽  
Diego Prada-Gracia ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Signal Transduction ◽  
Complex Behavior ◽  
Dipalmitoyl Phosphatidyl Choline ◽  
Extensive Analysis ◽  
Long Time ◽  
Dynamics Simulations ◽  
G Protein Coupled ◽  
Gpcr Signal ◽  
Histamine H3

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.

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

2019 ◽  
Author(s):  
L. D. Herrera-Zúñiga ◽  
L. M. Moreno-Vargas ◽  
L. Ballaud ◽  
J. Correa-Basurto ◽  
D. Prada-Gracia ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Signal Transduction ◽  
Complex Behavior ◽  
Dipalmitoyl Phosphatidyl Choline ◽  
Extensive Analysis ◽  
Long Time ◽  
Dynamics Simulations ◽  
G Protein Coupled ◽  
Gpcr Signal ◽  
Histamine H3

ABSTRACTIn 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.

scholarly journals Publisher Correction: Molecular dynamics of the histamine H3 membrane receptor reveals different mechanisms of GPCR signal transduction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Leonardo David Herrera-Zúñiga ◽  
Liliana Marisol Moreno‑Vargas ◽  
Luck Ballaud ◽  
José Correa‑Basurto ◽  
Diego Prada‑Gracia ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Signal Transduction ◽  
Membrane Receptor ◽  
Gpcr Signal ◽  
Histamine H3

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

2020 ◽  
Vol 21 (16) ◽  
pp. 5933 ◽  
Author(s):  
Mariona Torrens-Fontanals ◽  
Tomasz Maciej Stepniewski ◽  
David Aranda-García ◽  
Adrián Morales-Pastor ◽  
Brian Medel-Lacruz ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Data ◽  
Md Simulations ◽  
Full Potential ◽  
Missing Information ◽  
X Ray Crystallography ◽  
Cryo Electron Microscopy ◽  
G Protein Coupled ◽  
Gpcr Signal ◽  
Important Drug

G protein-coupled receptors (GPCRs) are implicated in nearly every physiological process in the human body and therefore represent an important drug targeting class. Advances in X-ray crystallography and cryo-electron microscopy (cryo-EM) have provided multiple static structures of GPCRs in complex with various signaling partners. However, GPCR functionality is largely determined by their flexibility and ability to transition between distinct structural conformations. Due to this dynamic nature, a static snapshot does not fully explain the complexity of GPCR signal transduction. Molecular dynamics (MD) simulations offer the opportunity to simulate the structural motions of biological processes at atomic resolution. Thus, this technique can incorporate the missing information on protein flexibility into experimentally solved structures. Here, we review the contribution of MD simulations to complement static structural data and to improve our understanding of GPCR physiology and pharmacology, as well as the challenges that still need to be overcome to reach the full potential of this technique.

scholarly journals Molecular Dynamics Simulations of G-Protein Coupled Receptor Lipid Interactions

2017 ◽  
Vol 112 (3) ◽  
pp. 386a
Author(s):  
George Hedger ◽  
Hsin-Yung Yen ◽  
Idlir Liko ◽  
Carol V. Robinson ◽  
Christian Siebold ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
Lipid Interactions ◽  
Dynamics Simulations ◽  
G Protein Coupled
Sign in / Sign up

Export Citation Format

Share Document