Cryo-EM Structures and AlphaFold3 Models of Histamine Receptors Reveal Diverse Ligand Binding and G Protein Bias.

ABSTRACT: Background: 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 Å 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

SUBMITTER: Chen A 

PROVIDER: S-EPMC11946611 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature