Fig. 4: Ligand pocket of H1R and H2R.

a 3D visualization showing detailed interactions between Histamine and the pocket residues of histamine receptors (from left to right panel: H1R, H2R, H3R, and H4R). Hydrogen bonds or polar interactions are depicted as red dashed lines, charge-charge interactions are depicted as yellow dashed lines, and red dots shown in the rightmost panel represent water molecules. Note that the primary nitrogen in the ethylamine chain of histamine is protonated and positively charged (marked with +), which forms electrostatic interactions between D^3.32 in H1R/H2R (marked with −), and E^5.46 in H3R/H4R (marked with −). In addition, the delta nitrogen in the imidazole ring of histamine could undergo protonation (marked with +), potentially enabling an electrostatic interaction with D^3.32 in H3R/H4R (marked with −). b Cross-sectional view of the ligand binding pockets in the Histamine-bound H1R-Gq, H2R-Gq, H3R-Gi, and H4R-Gi complexes (from left to right). Residues within the orthosteric pocket (OP), secondary binding pocket (SBP), and transmembrane subpocket (TMSP) are highlighted in brown, dark green, and magenta, respectively. c Barcode representation illustrating residues in the imidazole group recognition pocket (IGRP) of four histamine receptors (HRs). Note that Y^6.51 is a common residue among all HRs. H1R and H2R share a similar IGRP, differing only in unique residues: W^4.56 and N^5.46 in H1R, and D^5.42 in H2R. The IGRPs of H3R and H4R are identical.