Molecular basis of ligand binding and receptor activation at the human A(3) adenosine receptor

Zhang, L; Mobbs, JI; Bennetts, FM; Venugopal, H; Nguyen, ATN; Christopoulos, A; van der Es, D; Heitman, LH; May, LT; Glukhova, A; Thal, DM

Author(s): Zhang, L; Mobbs, JI; Bennetts, FM; Venugopal, H; Nguyen, ATN; Christopoulos, A; van der Es, D; Heitman, LH; May, LT; Glukhova, A; Thal, DM;
Details: Publication Year 2025-08-18,Volume 16,Issue #1,Page 7674
Journal Title: Nature Communications
Abstract: Adenosine receptors (ARs: A(1)AR, A(2A)AR, A(2B)AR, and A(3)AR) are crucial therapeutic targets; however, developing selective, efficacious drugs for them remains a significant challenge. Here, we present high-resolution cryo-electron microscopy (cryo-EM) structures of the human A(3)AR in three distinct functional states: bound to the endogenous agonist adenosine, the clinically relevant agonist Piclidenoson, and the covalent antagonist LUF7602. These structures, complemented by mutagenesis and pharmacological studies, reveal an A(3)AR activation mechanism that involves an extensive hydrogen bond network from the extracellular surface down to the orthosteric binding site. In addition, we identify a cryptic pocket that accommodates the N(6)-iodobenzyl group of Piclidenoson through a ligand-dependent conformational change of M174(5.35). Our comprehensive structural and functional characterisation of A(3)AR advances our understanding of adenosine receptor pharmacology and establishes a foundation for developing more selective therapeutics for various disorders, including inflammatory diseases, cancer, and glaucoma.
Publisher: Springer Nature
Research Division(s): Structural Biology
PubMed ID: 40825947
Publisher's Version: https://doi.org/10.1038/s41467-025-62872-x
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-62872-x
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-08-29 08:41:21

Last Modified: 2025-08-29 08:41:29