A basic molecular model for the H2 histamine receptor. Part 1

Abstract

A 3D model of the canine H2 receptor was built and analysed. This model was constructed using primary sequence comparisons and three-dimensional homology building with bacteriorhodopsin serving as a template. The energy analysis of the interaction between the N3H⁺ form and the N1H⁺ form of histamine with the receptor shows that both have the same binding affinity for the H2 receptor, but only the N3H⁺ form provokes structural changes. The calculated potential energies are consistent with the published binding data and suggest that Asp 98 is the principal residue for ligand recognition. On the basis of sequence alignment studies we postulate that Glu 270 in helix 7 may be important for activation of the H2 receptor. Docking studies of the N3H⁺ folded conformation in our model show that an intramolecular hydrogen bond between N3 and the amino group of the histamine molecule is broken, and the histamine then adopts a conformation similar to the N3H⁺ extended form to interact optimally with the H2 receptor. Mutations were made in the H2 receptor model to mimic published experimental point mutations. The interactions of the mutated receptor models with histamine are consistent with the experimental data.