Zhang Liudi, Mobbs Jesse I, Bennetts Felix M, Venugopal Hariprasad, Nguyen Anh T N, Christopoulos Arthur, van der Es Daan, Heitman Laura H, May Lauren T, Glukhova Alisa, Thal David M
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
Nat Commun. 2025 Aug 18;16(1):7674. doi: 10.1038/s41467-025-62872-x.
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.
腺苷受体（ARs：A1AR、A2AAR、A2BAR和A3AR）是关键的治疗靶点；然而，开发针对它们的选择性、有效药物仍然是一项重大挑战。在此，我们展示了人A2AAR处于三种不同功能状态下的高分辨率冷冻电镜（cryo-EM）结构：与内源性激动剂腺苷、临床相关激动剂匹可利定以及共价拮抗剂LUF7602结合。这些结构，辅以诱变和药理学研究，揭示了一种A2AAR激活机制，该机制涉及从细胞外表面到正构结合位点的广泛氢键网络。此外，我们通过M174的配体依赖性构象变化确定了一个容纳匹可利定N-碘苄基的隐蔽口袋。我们对A2AAR进行的全面结构和功能表征增进了我们对腺苷受体药理学的理解，并为开发针对包括炎症性疾病、癌症和青光眼在内的各种疾病的更具选择性的治疗方法奠定了基础。
