Michel Bouvier
Crédit : Amélie Philibert, Université de Montréal
Michel Bouvier, professor in the Department of Biochemistry and Molecular Medicine at the University of Montreal and General Director of the Institute for Research in Immunology and Cancer (IRIC) of UdeM, and his collaborators Madan Babu, researcher at the St. Jude Children’s Research Hospital, and Brian Kobilka, researcher at Stanford University, analyzed the molecular and structural characteristics dictating the ability of a ligand to activate a G protein-coupled receptor (GCPR). Because GPCRs represent the largest family of therapeutic targets, these works pave the way for the design of more effective drugs. The work, led by Franziska M. Heydenreich when she was a postdoctoral fellow in Michel Bouvier’s laboratory, is the subject of a publication in the journal Science.
More than 500 molecules naturally present 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 as 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.
Elucidating intramolecular information propagation relays
As is the case with a radio, each component of GPCRs has a role to play in signal transmission. Because GPCRs are composed of amino acids, the research team wanted to determine the contribution to signal propagation of each of the 412 amino acids in the β2-adrenergic receptor (β2AR), the adrenaline receptor used as a model in the study, by mutating them one by one.
Through this systematic approach, scientists were able to measure the power parameters (ligand concentration required to achieve the expected response) and efficiency (maximum response produced by a given ligand) for all created mutations. By overlaying this data with the three-dimensional structure of the β2AR receptor, the team was able to map the interactions inside the β2AR receptor that allow signal transmission.
Interestingly, only a fraction of the amino acids of the β2AR receptor have an effect on the measured pharmacological parameters. Among them, some influence power more, others efficiency. Still others act on both parameters at the same time. Therefore, some amino acids in a given protein sequence can have a specific effect on the pharmacological response.
“The originality of this study lies in the discovery of distinct mechanisms that selectively dictate the power or the pharmacological efficiency of GPCR-activating ligands, and this, in a semi-independent way,” says Michel Bouvier.
The integrated approach developed, which combines 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 power and efficiency.
About the study
The article “Molecular determinants of ligand efficacy and power in GPCR signaling“, by Franziska M. Heydenreich and colleagues, was published on December 22, 2023 in Science.
About IRIC
The Institute for Research in Immunology and Cancer (IRIC) of the University of Montreal, a research center and ultramodern training center, was created in 2003 to elucidate the mechanisms of cancer and accelerate the discovery of new, more effective therapies against this disease. IRIC operates on a unique model in Canada. Its innovative approach to research has already led to discoveries that will have a significant impact in the fight against cancer in the coming years.
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