Applied Crystallography

Biography

Biography: Hélène Déméné

Abstract

Opioid receptors (OR), members of the G protein-coupled receptor (GPCR) superfamily, constitute the major target for the treatment of pain[1]. The use of opioid drugs acting at these receptors is however a leading cause of death by overdose in Europe and North America. Our collaborators recently described the structure of an antagonist-bound inactive and agonist-bound conformation of the µOR[2],[3]. It demonstrated the key molecular determinants for ligand binding and activation process common to other GPCRs. However, much remains to be learned about the mechanisms by which different agonists can induce distinct levels of Gi protein activation and/or arrestin recruitment upon activation of µOR. Pharmacological and biophysical studies suggest that this versatility can be achieved through the structural plasticity of GPCRs4. In this work, we analyze the conformational landscape of the µOR in distinct pharmacological conditions (full and partial agonists, antagonist) using liquid-state NMR spectroscopy in light of the X-Ray structures. We also investigate the structure and dynamics changes upon binding the effector Gs protein and a mimetic nanobody thereof. Our results show that there is very weak allosteric coupling between the agonist binding pocket and G protein coupling interface. Furthermore, the analysis provides clues on the successive structural events leading to the full active conformation of oR [5]. We know extend this approach to biased ligands, that are able to elicit G-protein activation without arrestin activation. A better knowledge of the structural basis of all activation pathways for opioid drug efficacy may lead to new therapeutic approaches with limited side effects. [1] Melnikova I (2010) Pain market. Nat. Rev. Drug Discov. 9(8):589-590. [2] Manglik A, et al. (2012) Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature 485(7398):321-326. [3] Huang, W, et al. Nature. 2015,524(7565):315-2 [4] Ghanouni P, et al. (2001) Functionally different agonists induce distinct conformations in the G protein coupling domain of the beta 2 adrenergic receptor. J. Biol. Chem. 276(27):24433-24436. [5] Sounier, R., et al. (2015) Nature 524, 375-378.