Multi-scale dynamics of G-Proteins Coupled Receptors (GPCRs

Multi-scale dynamics of G-Proteins Coupled Receptors (GPCRs) and their protein partners.
Nicolas FLOQUET *, Maxime LOUET, Landry CHARLIER and Jean MARTINEZ
Institut des Biomolécules Max Mousseron (IBMM), CNRS UMR5247, Université Montpellier 1,
Université Montpellier 2, Faculté de Pharmacie, 15 Avenue Charles Flahault, B.P. 14491, 34093
Montpellier cedex 05, France. * [email protected]
G-proteins Coupled Receptors (GPCRs) are transmembrane receptors made of seven helical
segments. These receptors are highly attractive for the development of new drugs as almost 40% of
marketed drugs target one receptor of this large family of proteins.
From the extra-cellular binding of ligands to the intra-cellular interactions with their
privileged G-proteins partners, GPCRs encounter small to large conformational changes, necessary
for their activation cycle.
Since a few years, we have been interested in the computational studies of these receptors
combining different molecular mechanics techniques that include original normal modes analyses
1,2
, all atoms molecular dynamics simulations, and more recently coarse-grained representation of
the same systems. Docking studies are also performed taking advantage of this conformational
sampling to better predict the ligands:receptors interactions.
In my presentation, i will first describe how we have proposed an activation mechanism for
the human Ghrelin receptor 3, a food-stimulating GPCR.
An activation mechanism will then be discussed concerning the membrane-anchored
heterotrimeric G-proteins 4. Finally, I will describe how GDP release, the rate limiting activation
step of G-proteins, can occur in G-proteins at the molecular level 5.
Perspectives to this work concern the modelling of larger systems including both partners, e.g. the
GPCR:G-protein complex at proximity of the plasmic membrane.
(1) Floquet, N.; Marechal, J.-D.; Badet-Denisot, M.-A.; Robert, C. H.; Dauchez, M.; Perahia, D. FEBS
Lett 2006, 580, 5130-5136.
(2) Floquet, N.; Durand, P.; Maigret, B.; Badet, B.; Badet-Denisot, M.-A.; Perahia, D. J. Mol. Biol
2009, 385, 653-664.
(3) Floquet, N.; M’Kadmi, C.; Perahia, D.; Gagne, D.; Bergé, G.; Marie, J.; Banères, J.-L.; Galleyrand,
J.-C.; Fehrentz, J.-A.; Martinez, J. J. Mol. Biol 2010, 395, 769-784.
(4) Louet, M.; Perahia, D.; Martinez, J.; Floquet, N. J Mol Biol 2011.
(5) Louet, M.; Martinez, J.; Floquet, N., in revision.