DATE2025.06.27 #Press Releases

Elucidation of the Molecular Mechanisms Underlying G Protein Preferences across Histamine Receptors

Summary

A research group comprising Yuma Matsuzaki (graduate student), Fumiya K. Sano (Project Assistant Professor), and Professor Osamu Nureki from the Graduate School of Science, The University of Tokyo, along with Professor Asuka Inoue from the Graduate School of Pharmaceutical Sciences, Kyoto University, has elucidated the the determinant of G protein preferences in the histamine receptors H₁R and H₄R.

In this study, the team determined multiple structures of histamine receptor–G protein complexes using cryo-electron microscopy. By combining structural comparisons with mutational analyses and molecular dynamics simulations, they revealed that H₄R possesses distinct mechanisms of ligand recognition and receptor activation compared to H₁R. They also found that intracellular loop 2 of the receptor plays a crucial role in G protein preferences.

These findings provide deeper insight into the signaling mechanisms mediated by histamine and are expected to contribute to the development of novel anti-inflammatory and anti-allergic drugs targeting histamine receptors.

Figure: Schematic Diagram of the Interactions between H₁R/H₄R and G Protein

Journals

Journal name	Communications Biology
Title of paper	Structural insights into ligand recognition and G protein preferences across histamine receptor