Basal Histamine H 4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif.

Histamine H ₄ receptor (H ₄ R) orthologues are G-protein-coupled receptors (GPCRs) that exhibit species-dependent basal activity. In contrast to the basally inactive mouse H ₄ R (mH ₄ R), human H ₄ R (hH ₄ R) shows a high degree of basal activity. We have performed long-timescale molecular dynamics simulations and rigidity analyses on wild-type hH ₄ R, the experimentally characterized hH ₄ R variants S179M, F169V, F169V+S179M, F168A, and on mH ₄ R to investigate the molecular nature of the differential basal activity. H ₄ R variant-dependent differences between essential motifs of GPCR activation and structural stabilities correlate with experimentally determined basal activities and provide a molecular explanation for the differences in basal activation. Strikingly, during the MD simulations, F169 ^45.55 dips into the orthosteric binding pocket only in the case of hH ₄ R, thus adopting the role of an agonist and contributing to the stabilization of the active state. The results shed new light on the molecular mechanism of basal H ₄ R activation that are of importance for other GPCRs.
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