null Unravelling mechanisms for cardiovascular therapeutics
RI-MUHC researchers co-lead a team that combines novel pharmacology with structural biology and computational modelling to discover new domains within the AT1R receptor
Published today in Science Signaling, a new study by an international team of researchers may lead to better drugs for the treatment of cardiovascular diseases. Co-led by Stéphane Laporte, PhD, a senior scientist in the Metabolic Disorders and Complications Program at the Research Institute of the McGill University Health Centre (RI-MUHC), the team has discovered multiple mechanisms by which hormones and drugs can transmit information at the surface of a cell.
“Cells in the human body are surrounded by receptors on their surface. Many of these receptors are important for the activity of drugs and therapeutics because receptors receive and transmit signals that allow our cells, tissues and organs to produce specific physiological responses,” says Laporte, who is also Professor of Medicine in the Faculty of Medicine and Health Sciences at McGill University.
The team has successfully identified key domains and mechanisms within a specific kind of receptor known as Angiotensin II type 1 receptor, or AT1R. The newly identified domains within the AT1R receptor are responsible for binding with novel small molecules and transmitting specific signals, thus making them a promising potential target for new drugs.
Like other G protein-coupled receptors (GPCRs), AT1R is known to play a critical role in cardiovascular regulation, and is implicated in conditions such as congestive heart failure and preeclampsia. Drugs acting on this receptor can selectively engage certain cellular responses, but the mechanisms to promote specific activity are not fully understood.
“The breakthrough of our study lies in the revelation of previously unknown regions in the receptor, beyond the hormone binding site, that regulate the transmission of vital information,” says Yubo (Frank) Cao, co-first author on this publication and a PhD student in Stéphane Laporte’s laboratory at the time of this work. “We were surprised and excited to learn that drugs can communicate information via unsuspected regions of the receptors, outside of this known binding site.”
“We uncovered that proteins have multiple druggable binding sites that will allow us to use these methods to design drugs with lower side effects,” says Nagarajan Vaidehi, PhD, Professor and Chair of the Department of Computational and Quantitative Medicine at Beckman Research Institute of City of Hope in California, and co-corresponding author on this publication.
The team used cutting-edge biophysical and pharmacology approaches, combining an in-depth understanding of structural biology with innovative computational analysis.
“We have uncovered the intricate allosteric communication within the receptor, which dictates receptor responses to certain intracellular pathways,” adds Wijnand J.C. van der Velden, PhD, co-first author and a postdoctoral fellow in computational and quantitative medicine at Beckman Research Institute of City of Hope. “We also discovered that this allosteric communication follows diffuse pipelines in the receptor and involves unsuspected structural domains in the receptor.”
“This work opens exciting possibilities for developing new drugs to precisely modulate the activity of the AT1R receptor in cardiovascular diseases,” concludes Stéphane Laporte. “We look forward to our work playing a role in the development of new pharmacological therapeutics for these and other cardiovascular conditions with important implications for human health."
About the study:
The study Unraveling allostery within the angiotensin II type 1 receptor for Gαq and β-arrestin coupling was conducted by Yubo Cao, Wijnand J. C. van der Velden, Yoon Namkung, Anita K. Nivedha, Aaron Cho, Dana Sedki, Brian Holleran, Nicholas Lee, Richard Leduc, Sanychen Muk, Keith Le, Supriyo Bhattacharya, Nagarajan Vaidehi and Stéphane A. Laporte.
Science Signaling. DOI : 10.1126/scisignal.adf2173
The authors gratefully acknowledge funding from the Canadian Institutes of Health Research and the National Institutes of Health (NIH).
August 8, 2023