A COMPUTATIONAL MODEL OF THE ROLE OF IONIC-LOCK INTERACTIONS IN LIGAND RECOGNITION BY THE HUMAN C3a RECEPTOR

Computational techniques such as homology modeling and molecular dynamics were used to identify novel intramolecular ionic-lock interactions among key charged residues spanning the transmembrane helices and extracellular loops of human complement C3a receptor and the synthetically prepared human C3a receptor ligand SB290157. The results shed light on the active site of the human C3aR and the arginine specificity of the ligand. A strong ionic-lock region with interactions among the charged residues R161 (R4.64), E162 (ER4.65), R340 (R5.42), K96 (K3.36), D167 (D4.70), D417 (D7.35) and H418 (H7.36) is critical for the structural integrity of human C3aR. Results of docking both the stereoisomer of SB290157 with human C3aR indicate that the active site consist of the aromatic residues F107 (F3.37), Y160 (Y4.63), F345 (F5.47), W390 (W6.48), Y393 (Y6.51) and F396 (F6.54) together with the ionic-lock region and reveal the lack of stereospecific preference of human C3aR for SB290157. The active site features of human C3aR and the proposed ligand-binding region may permit the discovery of novel antagonists for C3aR as potential therapeutic agents for conditions such as asthma.