Cryo-EM structure of the human histamine H1 receptor/Gq complex
Ruixue Xia, Na Wang, Zhenmei Xu, Lu Yang, Jing Song, Anqi Zhang, Changyou Guo, Yuanzheng He
Abstract
Abstract 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.