• Study by IIT-Kanpur researchers published in the prestigious international journal Molecular Cell unravels a previously unknown mechanism that regulates an important class of drug targets known as G protein-coupled receptors

• It visualizes the cross talk between G protein-coupled receptors (GPCRs) involved in regulating heart function, blood pressure, mental disorders, and human behavior, and another type of molecules called arrestins that regulate the function of GPCRs

• The discovery has led to the identification of a novel mechanism responsible for regulating the function of GPCRs in human body, and it also opens up novel directions for improving the currently existing medicines and for discovering new medicines for several human disease conditions

• The researchers are currently working on novel drug discovery in collaboration with several international laboratories

Kanpur, 24 May 2023: A group of researchers led by Prof. Arun K Shukla in the Department of Biological Sciences and Bioengineering at the Indian Institute of Technology Kanpur (IIT-K) has unraveled a previously unknown mechanism that regulates an important class of drug targets known as G protein-coupled receptors. The discovery has important implications for not only understanding the fundamental mechanism of cellular signaling in our body but it also has potential to facilitate novel drug discovery for several human disease conditions. The study published in the May issue of the international journal, Molecular Cell has been conducted using a cutting-edge technology known as cryogenic-electron microscopy (cryo-EM).

The cells in our body are surrounded by a membrane that harbors a special type of protein molecules known as receptors. These receptors are important for our body to sense different chemical and hormones, and respond accordingly by activating specific physiological responses. One particular class of receptors known as G protein-coupled receptors (GPCRs), is involved in regulating heart function, blood pressure, mental disorders, and our behavior. Several drugs such as those used for depression, heart failure, cancer, and hypertension work by modulating these receptor proteins.

The function of GPCRs is regulated by another family of proteins in our body known as arrestins, which bind to GPCRs and control their function and physiological responses. However, a complete understanding of GPCR-arrestin interaction has been mostly elusive so far. The researchers have now visualized the cross-talk of GPCRs and arrestins in great detail using the cutting-edge technology, cryogenic-electron microscopy (cryo-EM). The same has allowed the team to discover a novel mechanism that is responsible for regulating the function of GPCRs in our body.

Says Prof Shukla, "This study has opened up novel directions for improving the currently existing medicines by lowering their side-effects, and also provides an opportunity for discovering new medicine for several human disease conditions. For example, the chemokine receptor that is one of the receptors investigated in this study has important roles in breast cancer progression while the complement receptors also investigated here are important targets for treating inflammatory disorders such as rheumatoid arthritis."

The researchers are now working in the direction of novel drug discovery in collaboration with several international laboratories including studies in animal models.

This study is led by Prof. Arun K. Shukla and is co-authored by PhD students Mr. Jagannath Maharana, Ms. Parishmita Sarma and Ms. Shirsha Saha, post-doctoral fellows Dr Ramanuj Banerjee and Dr Manish Yadav, and project fellows Mr. Sayantan Saha and Mr. Vinay Singh. The study also includes Dr Mohamed Chami from the University of Basel in Switzerland as a collaborator. This study is supported by the DBT Wellcome Trust India Alliance and Science and Engineering Research Board (SERB).

Dr. Shukla is also spearheading the establishment of a National cryo-EM facility at IIT Kanpur that is supported by SERB, and expected to be functional later this year.

Journal reference:

Shukla AK, Maharana J, Sarma P, Yadav MK, Saha S, Singh V, Saha S, Chami M, Banerjee R. “ Structural snapshots uncover a key phosphorylation motif in GPCRs driving β-arrestin activation”. 2023. Molecular Cell. May: https://doi.org/10.1016/j.molcel.2023.04.025

About IIT Kanpur:

Indian Institute of Technology (IIT) Kanpur was established on 2nd November 1959 by an Act of Parliament. The institute has a sprawling campus spread over 1055 acres with large pool of academic and research resources spanning across 19 departments, 22 centres, and 3 Interdisciplinary programs in engineering, science, design, humanities, and management disciplines with 540 full-time faculty members and approximately 9000 students. In addition to formal undergraduate and postgraduate courses, the institute has been active in research and development in areas of value to both industry and government.

For more information, visit www.iitk.ac.in.