Molecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor

Abstract

Histamine receptors are a group of G protein-coupled receptors (GPCRs) that play important roles in various physiological and pathophysiological conditions. Antihistamines that target the histamine H1 receptor (H1R) have been widely used to relieve the symptoms of allergy and inflammation. Here, to uncover the details of the regulation of H1R by the known second-generation antihistamines, thereby providing clues for the rational design of newer antihistamines, we determine the cryo-EM structure of H1R in the apo form and bound to different antihistamines. In addition to the deep hydrophobic cavity, we identify a secondary ligand-binding site in H1R, which potentially may support the introduction of new derivative groups to generate newer antihistamines. Furthermore, these structures show that antihistamines exert inverse regulation by utilizing a shared phenyl group that inserts into the deep cavity and block the movement of the toggle switch residue W4286.48. Together, these results enrich our understanding of GPCR modulation and facilitate the structure-based design of novel antihistamines.

Revealing Metabolic Dysregulation Induced by Polypropylene Nano- and Microplastics in Nile Tilapia via Noninvasive Probing Epidermal Mucus

“…Histamine is an important immune mediator that plays a critical role in allergic reactions and inflammatory processes. 27,28 Upregulation of histamine may indicate the presence of inflammation or immune activation within the tilapia epidermal mucus. 29,30 4-Hydroxynonenal (4-HNE) is a lipid peroxidation product formed during the oxidation of fatty acids, serving as a metabolic byproduct.…”

“…For example, upregulation of amino acid-related compounds such as N -methylhistidine, alpha-ketoisovaleric acid, and phenylalanine may affect amino acid synthesis, degradation, or transport processes, leading to abnormal amino acid metabolism. Histamine is an important immune mediator that plays a critical role in allergic reactions and inflammatory processes. , Upregulation of histamine may indicate the presence of inflammation or immune activation within the tilapia epidermal mucus. , 4-Hydroxynonenal (4-HNE) is a lipid peroxidation product formed during the oxidation of fatty acids, serving as a metabolic byproduct. , The upregulation of 4-HNE is often a consequence of oxidative stress and cell damage . Antimicrobial and antifungal functions are possessed by piscine epidermal mucus, which offers a protective layer for the fish against pathogenic microorganisms and bacteria from the external environment. , The reduced secretion of caprylic acid may decrease the ability of the body to resist microbes, aligning with the function of epidermal mucus .…”

Structural basis of ligand recognition and design of antihistamines targeting histamine H4 receptor

“…The active structure reveals a shrinkage of ligand binding pocket size via the ionic interaction of histamine with key residues in transmembrane helix 3, 6, and 7 (TM3,6 and 7), followed by an outward movement of TM6 to open the intracellular cavity for the G q -protein to engage the GPCR, as the main mechanism for H 1 R activation. Later, a cryo-electron microscopy (cryo-EM) structure of antagonist famotidine-bound H 2 R via a fusion strategy 12 and a crystal structure of antagonist PF03654746-bound H 3 R 13 were subsequently reported, revealing the inactive conformations of H 2 R and H 3 R. Most recently, the cryo-EM structures of apo and antihistamine-bound H 1 R were reported 14 .…”

Comprehensive mapping of histamine H1 receptor mRNA in the mouse brain

“…Histamine acts on the rhodopsin-like family of G protein-coupled receptors, which includes four distinct subtypes from H 1 receptor (H 1 R) to H 4 receptor (Hill et al, 1997;Wang et al, 2024). The H 1 R subtype, in particular, is coupled to G q/11 protein, triggering calcium release and the activation of protein kinase C (Haas & Panula, 2003).…”