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Cryo-EM structure of histamine H1 receptor Gq complex
Structural highlights
FunctionHRH1_HUMAN In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system. Publication Abstract from PubMedHistamine 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 alphaN-beta 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. Cryo-EM structure of the human histamine H(1) receptor/G(q) complex.,Xia R, Wang N, Xu Z, Lu Y, Song J, Zhang A, Guo C, He Y Nat Commun. 2021 Apr 7;12(1):2086. doi: 10.1038/s41467-021-22427-2. PMID:33828102[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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