Structural insights into ligand recognition and G protein preferences across histamine receptors

Histamine exerts critical physiological roles by activating four receptor subtypes, each exhibiting a specific G protein preference. Among these, the histamine H₄ receptor (H₄R) modulates chemotaxis and interferon production through G_i protein activation, suggesting its therapeutic potential. Despite its physiological significance, the mechanisms underlying H₄R signalling and G protein preference across histamine receptors remain poorly understood. Here, we present the cryo-electron microscopy structure of the H₄R-G_i complex, revealing unique mechanisms of histamine recognition and receptor activation. We further solved the structures of the histamine H₁ receptor (H₁R) bound to the non-canonical G proteins G_i and G_s. Through a combination of functional and computational analyses, we identified the intracellular loop 2 as a critical determinant of G protein preference in H₁R and H₄R. Collectively, our comprehensive study revealed the structural basis for distinct mechanisms of ligand recognition and receptor activation, offering a profound insight into G protein preference across receptor subtypes.