Cryo-EM structure of the human histamine H(1) receptor/G(q) complex

Histamine receptors play important roles in various pathophysiological conditions and are effective targets for anti-allergy treatment, however the mechanism of receptor activation remain elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human H(1)R in complex with a G(q) protein in an active conformation via a NanoBiT tethering strategy. The structure reveals that histamine activates receptor via interacting with the key residues of both transmembrane domain 3 (TM3) and TM6 to squash the binding pocket on the extracellular side and to open the cavity on the intracellular side for G(q) engagement in a model of “squash to activate and expand to deactivate”. The structure also reveals features for G(q) coupling, including the interaction between intracellular loop 2 (ICL2) and the αN-β junction of G(q/11) protein. The detailed analysis of our structure will provide a framework for understanding G-protein coupling selectivity and clues for designing novel antihistamines.