Michael Bouvier
Photo credit: Amélie Philibert, University of Montreal
Michel Bouvier, professor in the Department of Biochemistry and Molecular Medicine at the University of Montreal and director general of the Institute for Immunology and Cancer Research (IRIC) at UdeM, and his collaborators Madan Babu, researcher at St. Jude Children's Research Hospital, and Brian Kobilka, a researcher at Stanford University, analyzed the molecular and structural properties that determine a ligand's ability to activate a G protein-coupled receptor (GPCR). Since GPCRs represent the largest family of therapeutic targets, this work paves the way for the development of more effective drugs. The work carried out by Franziska M. Heydenreich during her time as a postdoctoral researcher in Michel Bouvier's laboratory is the subject of a publication in the journal Science.
More than 500 naturally occurring molecules in humans, such as hormones, and a third of drugs target GPCRs. Like a radio, GPCRs receive extracellular signals, decode them, and in turn transmit them into intracellular signals to selectively activate different signaling pathways. Metabolism, cell growth and immune responses are just a few examples of processes that can be regulated by GPCRs.
Elucidation of intramolecular information propagation relays
Like a radio, each component of RCPG plays a role in transmitting signals. Since GPCRs are made up of amino acids, the research team wanted to determine the contribution of each of the 412 amino acids of the β2-adrenergic receptor (β2AR), the adrenaline receptor used as a model in the study, to signal propagation by mutating one of them individually.
Through this systematic approach, scientists were able to measure the parameters potency (ligand concentration required to obtain the expected response) and efficiency (maximum response produced by a given ligand) for all mutations created. By overlaying this data with the three-dimensional structure of the receptor, the team was able to map the interactions within the β2AR receptor that enable signaling.
Interestingly, only a fraction of the amino acids of the β2AR receptor have an influence on the measured pharmacological parameters. Among them, some influence the performance more, others the efficiency. Still others affect both parameters at the same time. Certain amino acids of a particular protein sequence can therefore have a specific influence on the pharmacological response.
“The originality of this study lies in the discovery of different mechanisms that selectively determine, in a semi-independent manner, the potency or pharmacological activity of the ligands that activate GPCRs,” emphasizes Michel Bouvier.
The developed integrative approach, combining structural information and pharmacological measurements, is not limited to the study of the β2AR receptor. Applied to other GPCRs, it opens the possibility of developing more effective drugs by designing molecules with optimal potency and effectiveness.
About the study
The article “Molecular determinants of ligand potency and potency in GPCR signaling” by Franziska M. Heydenreich and colleagues appeared on December 22, 2023 in Science.
About IRIC
The Institute for Research in Immunology and Cancer (IRIC) at the University of Montreal was founded in 2003 as a state-of-the-art research and training center to elucidate the mechanisms of cancer and accelerate the discovery of new, more effective therapies against the disease. Illness. IRIC operates on a model unique to Canada. His innovative perspective on research has already enabled discoveries that will have significant impact on the fight against cancer in the years to come.