Cryo-EM structure of the human histamine H1 receptor/Gq complex

Ruixue Xia, Na Wang, Zhenmei Xu, Yang Lu, Jing Song, Anqi Zhang, Changyou Guo and Yuanzheng He ()
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Ruixue Xia: Harbin Institute of Technology
Na Wang: Harbin Institute of Technology
Zhenmei Xu: Harbin Institute of Technology
Yang Lu: Harbin Institute of Technology
Jing Song: Harbin Institute of Technology
Anqi Zhang: Harbin Institute of Technology
Changyou Guo: Harbin Institute of Technology
Yuanzheng He: Harbin Institute of Technology

Nature Communications, 2021, vol. 12, issue 1, 1-9

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 H1R in complex with a Gq 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 Gq engagement in a model of “squash to activate and expand to deactivate”. The structure also reveals features for Gq coupling, including the interaction between intracellular loop 2 (ICL2) and the αN-β junction of Gq/11 protein. The detailed analysis of our structure will provide a framework for understanding G-protein coupling selectivity and clues for designing novel antihistamines.

Date: 2021
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DOI: 10.1038/s41467-021-22427-2

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