Allosterism in human complement component 5a (<sup>h</sup>C5a): a damper of C5a receptor (C5aR) signaling

<p>The phenomena of allosterism continues to advance the field of drug discovery, by illuminating gainful insights for many key processes, related to the structure–function relationships in proteins and enzymes, including the transmembrane G-protein coupled receptors (GPCRs), both in normal as well as in the disease states. However, allosterism is completely unexplored in the native protein ligands, especially when a small covalent change significantly modulates the pharmacology of the protein ligands toward the signaling axes of the GPCRs. One such example is the human C5a (<sup>h</sup>C5a), the potent cationic anaphylatoxin that engages C5aR and C5L2 to elicit numerous immunological and non-immunological responses in humans. From the recently available structure–function data, it is clear that unlike the mouse C5a (<sup>m</sup>C5a), the <sup>h</sup>C5a displays conformational heterogeneity. However, the molecular basis of such conformational heterogeneity, otherwise allosterism in <sup>h</sup>C5a and its precise contribution toward the overall C5aR signaling is not known. This study attempts to decipher the functional role of allosterism in <sup>h</sup>C5a, by exploring the inherent conformational dynamics in <sup>m</sup>C5a, <sup>h</sup>C5a and in its point mutants, including the proteolytic mutant <i>des</i>-Arg<sup>74</sup>-<sup>h</sup>C5a. Prima facie, the comparative molecular dynamics study, over total 500 ns, identifies Arg<sup>74</sup>-Tyr<sup>23</sup> and Arg<sup>37</sup>-Phe<sup>51</sup> “cation-π” pairs as the molecular “allosteric switches” on <sup>h</sup>C5a that potentially functions as a damper of C5aR signaling.</p>