IIT Kanpur Team Decodes How Immune Receptor C5aR2 Differs from Its Counterpart

A research team at IIT Kanpur headed by Professor Arun K. Shukla has identified the molecular mechanisms that explain the unusual signalling behaviour of C5aR2, an immune receptor that has long mystified the scientific community. Through cryogenic-electron microscopy (cryo-EM), the scientists determined why this receptor operates distinctly from its closely related relative, C5aR1, and created a compound that specifically binds to C5aR2, opening new possibilities for immune system research and therapeutic development.

The complement system represents the body's primary immune defence mechanism against harmful pathogens such as bacteria and viruses. This system comprises various proteins and enzymes that work to neutralise and eliminate infectious agents. When the complement system is activated, it releases small signalling proteins that trigger a controlled inflammatory cascade at sites of infection or tissue damage. These signalling molecules are termed complement anaphylatoxins and they engage specific receptors present on immune cell surfaces.

The complement protein C5a interacts with two separate membrane receptors: C5aR1 and C5aR2. While scientists have long understood the structure and function of C5aR1, C5aR2 has remained enigmatic. The key difference lies in their signalling mechanisms—C5aR1 activates well-established cellular pathways, whereas C5aR2 operates through unconventional signalling routes. Until now, the precise structural basis for this functional distinction has remained unclear because the atomic-level details of C5aR2 have been difficult to obtain.

Through cryo-EM analysis, the research team observed that although C5aR2's external-facing portion closely resembles that of C5aR1, its internal-facing region displays significant structural differences. This distinction prevents C5aR2 from engaging the standard signalling pathways that C5aR1 and other similar receptors use. Instead, the receptor's extended intracellular region interacts with alternative cellular partners, enabling it to signal through different mechanisms.

Drawing on these atomic-level findings, the research team synthesised a novel compound designated R8Y, which selectively targets C5aR2 without attaching to C5aR1. This development marks a substantial breakthrough, as it enables researchers to precisely evaluate the distinct roles these two receptors play in complement activation. Such selective targeting is expected to accelerate the development of new therapeutic agents that can modulate these receptors with greater precision. The team plans to advance this work by testing R8Y in animal models, with the ultimate objective of creating more effective and safer treatments.

The laboratory team contributing to this research included Divyanshu Tiwari, Annu Dalal, Sudha Mishra, Manish Yadav, Nabarun Roy, Manisankar Ganguly, Nilanjana Banerjee, and Dr. Ramanuj Banerjee. International collaborators included researchers from The University of Queensland in Australia, the University of Tokyo, and Kyoto University in Japan.

The work received funding from multiple sources including the DBT Wellcome Trust India Alliance, Anusandhan National Research Foundation (ANRF), Department of Science and Technology (DST), Indian Council of Medical Research (ICMR), and IIT Kanpur.