A team of researchers led by Prof Arun K Shukla from the Department of Biological Sciences and Bioengineering, Indian Institute of Technology-Kanpur, has discovered the molecular mechanism of complement receptor activation and signalling, which is a vital part of our immune response. The study has been published in the international scientific journal Cell.

The team based their research on the complement system and its dependence on molecules called anaphylatoxins, like C3a and C5a, which interact with specific receptors known as C3aR and C5aR1. They tried to understand the process of working of the receptors, including how they recognize their targets, activate, and control signalling, which have largely remained a mystery.

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The researchers used a powerful imaging technique called cryo-EM in the study to reveal the inner workings of these receptors when they are activated by natural and synthetic compounds. They have discovered unique binding pockets where anaphylatoxins attach to these receptors, shedding light on how the receptors become activated and engage with signalling proteins.

Additionally, the study also uncovered a natural mechanism where C5a’s inflammatory response is reduced through the removal of a specific part of the molecule. It also identified a peptide that selectively activates C3aR, demonstrating that the receptors can respond differently to various compounds.

In essence, this research provides a clearer understanding of how anaphylatoxin receptors function, which are important drug targets for inflammatory disorders, such as arthritis, asthma, sepsis, and many more. This study has important implications for novel drug discovery in several human disease conditions.

Apart from Prof Arun K Shukla the team comprised Manish K Yadav, Department of BSBE IIT-K; Jagannath Maharana, Department of BSBE IIT-K; Ramanuj Banerjee, Department of BSBE IIT-K; Ravi Yadav, Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California; and Cornelius Gati, Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California.