Evolution, Structure and fonction of GPCRs

 Marie Chabbert, CRHC CNRS

marie.chabbert@univ-angers.fr

Team members 

Marie Chabbert, Ph.D., CRHC CNRS

Asma Tiss, Ph.D. student (Angers-Carthage)

Rym Ben Boubaker, Ph.D. student (Angers)

Key words : GPCR, molecular evolution, molecular modeling and simulations, angiotensin II receptors.

State-of-the-art and objectives

G protein coupled receptors (GPCRs) play a key role in vascular regulation, either directly through receptors of vasoactive peptides such as AT1, AT2 and MAS or indirectly through the immune response (e.g chemokine receptors), adaptive response to stress (catecholamine receptors) and endocrine regulation of the metabolic control.

Our objective is a better understanding of the molecular mechanisms leading to GPCR activation and functional selectivity (activation of a specific pathway), with a long term aim in drug design.

Our approach is based on the coupling between molecular dynamics simulations and evolutionary information. Analysis of evolution reveals positions whose mutation was crucial for the evolution and divergence of GPCR families and thus may have an important role in receptor specificity and mechanism of action.

Presently, we are focusing on the molecular mechanisms leading to the activation and biased signaling of the Angiotensin II receptors AT1 and AT2 in response to ligand binding or physical stimuli. More precisely, we aim at answering the following questions:

1. What are the effects of mechanical stress (pressure, tension, flow shear) and membrane composition on receptor activation?
2. What is the role of the sodium ion in the activation mechanism and biased signaling?
3. What are the conformational ensembles sampled by the ligand cavity upon binding of different effectors? Do they correlate with the conformations observed upon binding of biased ligands?

The answers to these questions aim at understanding the molecular basis of receptor activation towards specific pathways and the putative role of sodium ions in this mechanism. The capability to link distinct conformations to the activation of specific pathways is instrumental in developing drugs that target distinct states to obtain different desirable downstream functions.

Main results from last five years

1. We have shown that the evolution of the sodium binding site is a key determinant of the functional evolution of GPCRs from the chemotaxic receptor family (Taddese et al., 2018).
2. We have shown that the N3.35 residue, a sequence pattern characteristic of chemotaxic receptors, plays an allosteric role in the mechanism of CXCR4 activation (Taddese et al. 2020).
3. We have developed Bios2cor, an R package aimed at analyzing correlated sidechain motions during MD simulations.

Recent publications

• Homology modeling in the twilight zone: Improved accuracy by sequence space analysis. Ben Boubaker R, Tiss A, Henrion D and Chabbert M. Methods Mol Bio, in press.
• Homology modeling of class A G-protein-coupled receptors in the age of the structure boom. Tiss A, Ben Boubaker R, Henrion D, Guissouma H and Chabbert M. Methods Mol Biol, in press.
• Deciphering collaborative sidechain motions in proteins during molecular dynamics simulations. Taddese B, Garnier A, Abdi H, Henrion D, Chabbert M (2020) Sci Rep, 10:15901.
• Evolution of chemokine receptors is driven by mutations in the sodium binding site. Taddese B, Deniaud M, Garnier A, Tiss A, Guissouma H, Abdi H, Henrion D, Chabbert M (2018) PLoS Comput Biol  14(6):e1006209.
• Molecular Insights into the Transmembrane Domain of the Thyrotropin Receptor. Chantreau V., Taddese B., Munier M., Gourdin L., Henrion D., Rodien P. and Chabbert M. (2015) Plos One 10:e0142250.

Softwares

Bios2cor. Authors: B Taddese, A Garnier, M Deniaud, M Chabbert. Version 2.2 published on 20/10/02, initial version published on 2017/08/24 (https://cran.r-project.org/).

Bios2mds. Authors: J Pele, JM Becu, R Ben Boubaker, H Abdi, M Chabbert. Version 1.2.3 published on 20/04/07. Initial version published on 11/12/27 (https://cran.r-project.org/).