9l42
Cryo-EM structure of human histamine receptor H4R in complex with agonist histamine and Gi proteins
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedBackground: The four subtypes of G protein-coupled receptors (GPCRs) regulated by histamine play critical roles in various physiological and pathological processes, such as allergy, gastric acid secretion, cognitive and sleep disorders, and inflammation. Previous experimental structures of histamine receptors (HRs) with agonists and antagonists exhibited multiple conformations for the ligands and G protein binding. However, the structural basis for HR regulation and signaling remains elusive. Methods: We determined the cryo-electron microscopy (cryo-EM) structure of the H4R-histamine-Gi complex at 2.9 A resolution, and predicted the models for all four HRs in the ligand-free apo and G protein subtype binding states using AlphaFold3 (AF3). Results: By comparing our H4R structure with the experimental HR structures and the computational AF3 models, we elucidated the distinct histamine binding modes and G protein interfaces, and proposed the essential roles of Y(6.51) and Q(7.42) in receptor activation and the intracellular loop 2 (ICL2) in G protein bias. Conclusions: Our findings deciphered the molecular mechanisms underlying the regulation of different HRs, from the extracellular ligand-binding pockets and transmembrane motifs to the intracellular G protein coupling interfaces. These insights are expected to facilitate selective drug discovery targeting HRs for diverse therapeutic purposes. Cryo-EM Structures and AlphaFold3 Models of Histamine Receptors Reveal Diverse Ligand Binding and G Protein Bias.,Chen A, Su C, Zhang Z, Zhang H Pharmaceuticals (Basel). 2025 Feb 21;18(3):292. doi: 10.3390/ph18030292. PMID:40143071[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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