A group of researchers led by Professor Arun K. Shukla in the Department of Biological Sciences and Bioengineering at the Indian Institute of Technology Kanpur (IIT-K) has uncovered a previously unknown mechanism regulating an important class of drug targets known as G protein-coupled receptors.
This discovery has important implications not only for understanding the underlying mechanism of cellular signaling in the human body, but also has the potential to facilitate the discovery of new drugs for many human disease conditions. The study published in the May issue of molecular cellusing an innovative technique known as cryo-electron microscopy (cryo-EM).
The cells in our bodies are surrounded by a membrane that contains a special type of protein molecule known as a receptor. These receptors are important for the body to sense various chemicals and hormones, and to respond accordingly by activating specific physiological responses. A specific class of receptors, known as G protein-coupled receptors (GPCRs), are involved in regulating heart function, blood pressure, mental disorders, and our behaviour. Many drugs, such as those used to treat depression, heart failure, cancer, and high blood pressure, work by modifying these receptor proteins.
The function of GPCRs is regulated by another family of proteins in the body known as stop, which bind to GPCRs and control their functions and physiological responses. However, a full understanding of the GPCR-stopin interaction has been mostly elusive until now. Researchers have now visualized the cross-talk of GPCRs and suspensions in great detail using a new technology, cryo-electron microscopy (cryo-EM). This allowed the team to discover a new mechanism responsible for regulating GPCR function in the body.
Prof. Shukla says, “This study has opened up new directions for improving existing drugs by reducing their side effects and also provides an opportunity for new drug discovery for many human disease conditions. For example, chemokine receptors which is one of the receptors examined in this study They have important roles in the development of breast cancer, while the complement receptors examined here are important targets for the treatment of inflammatory disorders such as rheumatoid arthritis.”
Researchers are now working towards discovering new drugs in collaboration with several international laboratories, including studies in animal models.
This study was led by Professor Aaron K. Shukla and co-authored Ph.D. Students Mr. Jagannath Maharana, Ms. Parishmita Sarma and Ms. Shersha Saha, Postdoctoral Fellows Dr. Ramanoj Banerjee and Dr. Manish Yadav, Project Colleagues Mr. Sayanthan Saha and Mr. Vinay Singh. The study also includes Dr. Mohamed El-Shamy from the University of Basel in Switzerland as a collaborator.
Jagannath Maharana et al, Structural snapshots reveal the key phosphorylation motif in GPCRs driving β-stopin activation, molecular cell (2023). doi: 10.1016/j.molcel.2023.04.025
Provided by Indian Institute of Technology Kanpur
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