Fig. 8: ICL3, determinant for selective coupling of H2R to Gs and Gq.
From: Structural basis of ligand recognition and activation of the histamine receptor family
a Superposition of H2R-Gs (green-blue) and H2R-Gq (dark gray-wheat) complex based on the transmembrane helices bundle. b Barcode representation illustrates the interaction patterns at the interface between the receptor and their respective G proteins in the cryo-EM structures of H2R-Gs, H2R-Gsq, and computationally simulated H2R-Gq complexes. Common residues are indicated by cyan circles, residues showing unique interaction with Gq are indicated by light green circles, residues showed unique interaction with MD Gq are indicated by purple circles, residues showing unique interaction with Gs are indicated by orange circles, and residues that show no interaction with G proteins are depicted as white circles. c 3D representation illustrating detailed interactions between residues in Gαs (upper panel) and Gαq (lower panel) with the residues of H2R. Hydrogen bonds are shown as red dashed lines. d Average root mean square deviation (RMSD) values of ICL3 in H2R-Gq and H2R-Gs complexes during 200 ns molecular dynamics (MD) simulations. e Detailed interactions between W222ICL3 on ICL3 of H2R and Gs subunit (left panel), and Gq subunit (right panel). Representative conformations of the binding of W222ICL3 in H2R to Gq were obtained from molecular dynamics simulations. Note that D315 and P318 in Gαq are the equivalent residues of R347 and T350 in Gαs. Hydrogen bond is depicted as a red dashed line. f, g Representative concentration-dependent response curves of H2R and its W222ICL3V and W222ICL3A mutants in response to histamine using the Gαs-Gγ dissociation assay (f) and the Gαq-Gγ dissociation assay (g). The pEC50 and Emax values are provided in Supplementary Table 5. Data from three independent experiments are presented as the mean ± SEM (n = 3).
