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Publication Abstract from PubMed

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 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.