Faculty Seminar
By Prof. Michel Bouvier
Title:
Emerging paradigms in G proteincoupled receptors (GPCRs) signaling and their implications for drug discovery
Date &Time:
May 29, 2022
12:15
Location:
Sfadia Auditorium, Multipurpose building
Prof. Michel Bouvier
Institute for Research in Immunology and Cancer (IRIC) of the Université de Montréal (UdeM)
G protein-coupled receptors (GPCRs) represent the largest family of proteins involved in signal transduction across biological membranes. As such, they are the target of more than 30% of existing drugs and remain top targets for the development of new ones. It is now clear that GPCRs are not unidimensional switches that turn ‘on’ or ‘off’ a single signaling pathway. Instead, each receptor can engage multiple signaling partners that can engage various downstream effector systems. Individual ligands can have differential efficacies toward specific subsets of the signaling effector repertoire engaged by a given receptor. This phenomenon, known as ligand-biased signaling or functional selectivity, opens new opportunities for the development of drugs targeting therapeutically relevant pathways while sparing those leading to undesirable effects. Yet, this pluri-dimensional nature of signaling efficacy presents a challenge to establish the complete signaling profile of drugs and to understand the structural basis of GPCR functional selectivity. Using a collection of bioluminescence resonance energy transfer (BRET)-based biosensors and imaging, we characterized the pluridimensional signaling profiles of many GPCRs and monitored the spatiotemporal signal propagation into distinct intracellular compartments. Computer-assisted analysis of the diverse signaling profiles observed allows the clustering of compounds into different groups permitting the association of specific signaling signatures with distinct functional outcomes. Analyzing the effects of receptor mutations on the signaling profiles combined with molecular modeling is starting to unravel the structural determinants linking the binding of biased ligands to the activation of specific signaling effectors. These studies open new avenues for the rational design of biased ligands with desired signaling properties.
Institute for Research in Immunology and Cancer (IRIC) of the Université de Montréal (UdeM)
G protein-coupled receptors (GPCRs) represent the largest family of proteins involved in signal transduction across biological membranes. As such, they are the target of more than 30% of existing drugs and remain top targets for the development of new ones. It is now clear that GPCRs are not unidimensional switches that turn ‘on’ or ‘off’ a single signaling pathway. Instead, each receptor can engage multiple signaling partners that can engage various downstream effector systems. Individual ligands can have differential efficacies toward specific subsets of the signaling effector repertoire engaged by a given receptor. This phenomenon, known as ligand-biased signaling or functional selectivity, opens new opportunities for the development of drugs targeting therapeutically relevant pathways while sparing those leading to undesirable effects. Yet, this pluri-dimensional nature of signaling efficacy presents a challenge to establish the complete signaling profile of drugs and to understand the structural basis of GPCR functional selectivity. Using a collection of bioluminescence resonance energy transfer (BRET)-based biosensors and imaging, we characterized the pluridimensional signaling profiles of many GPCRs and monitored the spatiotemporal signal propagation into distinct intracellular compartments. Computer-assisted analysis of the diverse signaling profiles observed allows the clustering of compounds into different groups permitting the association of specific signaling signatures with distinct functional outcomes. Analyzing the effects of receptor mutations on the signaling profiles combined with molecular modeling is starting to unravel the structural determinants linking the binding of biased ligands to the activation of specific signaling effectors. These studies open new avenues for the rational design of biased ligands with desired signaling properties.