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

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.

Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

“…In 2020 alone, new structures of 34 GPCR–Gs complexes, 19 GPCR-Gi/o complexes, and one GPCR-Gq/11 complex were published ( , access date 8 October 2021 [ 58 ]), providing valuable atomic-level insights into the binding interface of GPCRs with G proteins from different major families. Another milestone in histamine receptor research was the resolution of the first active structure of the histamine H 1 receptor in complex with Gq in 2021 [ 60 ]. Nevertheless, static structures alone do not allow us to map the dynamics of a GPCR–G protein interaction, and only complexes of primary coupling GPCRs and G proteins are available so far.…”

Food Intolerance: The Role of Histamine

“…Nonslow-type hypersensitivity reactions (erythema, pruritus, and edema) can be caused by H1R activation [45]. Histamine activates H1R through the Gαq/11 protein, triggering a cascade of transformations through the activation of phospholipase C and increasing Ca 2+ evels [46,47]. As a consequence, histamine causes contraction of airway smooth muscle, increases vascular permeability, and induces the production of prostacyclin-and platelet-activating factor [48].…”

Histamine: A Bacterial Signal Molecule

“…The TlpQ-LBD is composed of two structural α/β modules, and histamine was bound at the membrane distal module, like in the very large majority of other characterized dCache domains [59,[65][66][67][68]. The molecular detail of histamine recognition by human receptors has recently been deciphered by reporting three dimensional structures of the Histamine H1 receptor [69] and the β3 GABA A receptor in a complex with histamine [70] (Figure 2). The comparison of TlpQ-LBD with the two human receptors thus shows that the proteins involved in histamine sensing in bacteria and humans are entirely different.…”

“…Bound histamine is shown in stick mode in the lower part of the figure. These structures have been published in [23,69,70]. (B) Zoom on the histamine binding sites of the receptors shown above.…”