Kanpur: Researchers at IIT Kanpur, led by Professor Arun K Shukla, have uncovered the molecular basis underlying the atypical signalling behaviour of C5aR2, an immune receptor that has puzzled scientists for years.

Using cryogenic-electron microscopy (cryo-EM), the team revealed why C5aR2 functions differently from its closely related counterpart, C5aR1, and developed a molecule that selectively targets it, advancing efforts to better understand immune signalling and drug design.

Considered as the first line of defence against pathogenic infections, including deadly bacteria and viruses, it is the body's complement system, which involves a series of proteins and enzymes to clear the pathogens. As part of this mechanism, some small proteins are released to elicit a controlled inflammatory response at the site of infection or injury. These are known as complement anaphylatoxins, and they activate a specific type of receptor known as complement anaphylatoxin receptors expressed in the membrane of our immune cells.

The complement anaphylatoxin C5a activates two distinct cell membrane receptors known as C5aR1 and C5aR2. While the structure and function of C5aR1 have been well known, the C5aR2 has been a mysterious receptor. This is primarily due to the fact that C5aR1 signals through the canonical pathways in the cells, but C5aR2 uses a non-canonical mechanism.

However, the underlying mechanism of this functional divergence has remained elusive so far, as it has not been possible to visualise the atomic details of this receptor so far.

Using cryogenic-electron microscopy (cryo-EM), the researchers observed that while the part of the receptor facing the extracellular side is very similar to that of C5aR1, the part facing the cell interior is structurally distinct.

As a result, it fails to communicate with the canonical signalling mechanisms utilised by C5aR1 and other GPCRs. However, the distal sequence of the receptor is able to engage non-canonical partners within cells and thereby signal through alternative mechanisms.

Using the atomic details of C5aR2, the authors developed a new molecule termed R8Y, which is selective for C5aR2 and does not bind to C5aR1. This represents a significant advance in the field as it allows a precise assessment of the role of these two receptors in complement activation mechanisms. It is likely to facilitate the more accurate design of novel drug molecules activating these receptors in a selective manner. The scientists are now gearing up to test the molecule in animal models with a long-term goal to develop safer and better therapeutics.

Contributors to the study from Professor Shukla's laboratory included 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 in Australia, the University of Tokyo, and Kyoto University in Japan.

The study was supported by 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.

This report was published from a syndicated wire feed. Apart from the headline, the EdexLive Desk has not edited the copy.