9L42

Cryo-EM structure of human histamine receptor H4R in complex with agonist histamine and Gi proteins

Summary for 9L42

• Entry DOI: 10.2210/pdb9l42/pdb
• EMDB information: 62803
• Descriptor: Histamine receptor H4R, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• Functional Keywords: gpcr, histamine h4r receptor, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 156637.53

Authors

Chen, A.,Zhang, H. (deposition date: 2024-12-19, release date: 2025-10-22)

Primary citation

Chen, A.,Su, C.,Zhang, Z.,Zhang, H.
Cryo-EM Structures and AlphaFold3 Models of Histamine Receptors Reveal Diverse Ligand Binding and G Protein Bias.
Pharmaceuticals, 18:-, 2025

PubMed Abstract: 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. 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). 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 and Q in receptor activation and the intracellular loop 2 (ICL2) in G protein bias. 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.

PubMed: 40143071
DOI: 10.3390/ph18030292

Experimental method

ELECTRON MICROSCOPY (2.9 Å)