Scientists at IIT Kanpur have discovered how a little-known immune system receptor works, solving a problem that has vexed researchers for years and helping to improve drug targeting.The research, led by Professor Arun K Shukla, focused on a receptor called C5aR2, which plays a role in the body’s immune response. While a similar receptor called C5aR1 has been studied in detail, scientists have struggled to understand why C5aR2 behaves differently even though they appear to be closely related.The body’s complement system is one of the first lines of defense against bacterial and viral infections. As part of this process, certain proteins trigger inflammation to help the body fight infection. These proteins activate receptors on immune cells, including C5aR1 and C5aR2.The researchers say that C5aR1 follows normal signaling processes within cells. However, C5aR2 uses a different pathway, and the reasons behind this difference are still unclear.The IIT Kanpur team studied the receptor in detail using cryo-electron microscopy (cryo-EM). They found that while the outside of C5aR2 looked very similar to C5aR1, the inside of the receptor had a different structure. Therefore, C5aR2 is unable to communicate through the same signaling pathways used by C5aR1 and many other receptors. Instead, it uses alternative pathways within the cell.Based on these findings, the researchers developed a new molecule called R8Y. The molecule selectively targets C5aR2 but does not attach to C5aR1. Scientists say this could help them better understand the different roles of the two receptors and support the development of more precise drugs in the future.The team plans to test the molecule in animal models as a next step in developing safer, more effective treatments.The study involved researchers from Professor Shukla’s laboratory, including Divyanshu Tiwari, Annu Dalal, Sudha Mishra, Manish Yadav, Nabarun Roy, Manisankar Ganguly, Nilanjana Banerjee and Dr. Ramanuj Banerjee. The research was conducted in collaboration with the University of Queensland, the University of Tokyo and Kyoto University.This work was supported by the Department of Biotechnology (DBT), Wellcome Trust India Alliance, Anusandhan National Research Foundation (ANRF), Department of Science and Technology (DST), Indian Council of Medical Research (ICMR) and Indian Institute of Technology Kanpur.
