9EBH

Human adenosine A3 receptor Gi1 complex bound to adenosine

Summary for 9EBH

• Entry DOI: 10.2210/pdb9ebh/pdb
• EMDB information: 47879
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Antibody fragment scFv16|Mus musculus (10090), ... (6 entities in total)
• Functional Keywords: g protein-coupled receptor, adenosine binding, seven transmembrane protein, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 154484.22

Authors

Zhang, L.,Mobbs, J.I.,Glukhova, A.,Thal, D.M. (deposition date: 2024-11-12, release date: 2025-08-20, Last modification date: 2025-09-03)

Primary citation

Zhang, L.,Mobbs, J.I.,Bennetts, F.M.,Venugopal, H.,Nguyen, A.T.N.,Christopoulos, A.,van der Es, D.,Heitman, L.H.,May, L.T.,Glukhova, A.,Thal, D.M.
Molecular basis of ligand binding and receptor activation at the human A 3 adenosine receptor.
Nat Commun, 16:7674-7674, 2025

PubMed Abstract: Adenosine receptors (ARs: AAR, AAR, AAR, and AAR) 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 AAR 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 AAR 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-iodobenzyl group of Piclidenoson through a ligand-dependent conformational change of M174. Our comprehensive structural and functional characterisation of AAR 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.

PubMed: 40825947
DOI: 10.1038/s41467-025-62872-x

Experimental method

ELECTRON MICROSCOPY (3.6 Å)