Abstract

The complement peptide receptor C5aR, otherwisely known as the anaphylatoxin receptor is one of the two major GPCRs, known in the human genome that interact with the hC5a, the most potent proinflammatory polypeptide of the complement system. The interaction is known to trigger diverse non-immunological and immunological responses in several tissues and thus have been tagged “druggable” by the pharma-majors for discovery of potential therapeutics. In our quest toward understanding the pharmacology of hC5a-C5aR interaction better, we have recently hypothesized that hC5a can be allosteric and have identified a pair of “allosteric switches” on hC5a that potentially modulate the C5aR signaling. In addition, we have generated the ligand free structure of C5aR, including the “two-site” binding model complexes of C5aR bound to the native agonist hC5a and the engineered antagonist A8, derived from hC5a at an atomistic resolution, demonstrating the plausible “orthosteric” site2 at the ECS of C5aR. It is noteworthy that the recently reported experimental structure of thermostabilized / engineered C5aR (StaR) in complex with known ligands provide an excellent validation to our reported model structure of C5aR. Moving forward, we have now generated the “molecular complex” of hC5a-C5aR-G protein, which has been useful in providing mechanistic insights into the activation of C5aR in structural terms and has helped us to identify promising drug like molecules as “neutraligands”, which can potentially neutralize the function of hC5a by binding to the hot spots, as observed in case of targeted antibodies. Interestingly, the ongoing pilot studies in the lab strongly support the hypothesis, and we believe that the study will open new avenues for further design and discovery of potential leads, optimizable as future drugs, targeting the hC5a-C5aR signaling axes.