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Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A2 receptors

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Abstract

The adenosine subfamily G protein-coupled receptors A2AR and A2BR have been identified as promising cancer immunotherapy candidates. One of the A2AR/A2BR dual antagonists, AB928, has progressed to a phase II clinical trial to treat rectal cancer. However, the precise mechanism underlying its dual-antagonistic properties remains elusive. Herein, we report crystal structures of the A2AR complexed with AB928 and a selective A2AR antagonist 2–118. The structures revealed a common binding mode on A2AR, wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets. In contrast, the cAMP assay and A2AR and A2BR molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A2BR. Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A2BR pocket, while 2–118 did not due to intrinsic differences. This disparity potentially accounted for the difference in inhibitory efficacy between A2BR and A2AR. This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A2AR/A2BR for cancer therapy.

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Data availability

Atomic coordinates and structure factors for the A2BR-AB928 and A2BR-2-118 structures have been deposited in the Protein Data Bank with identification codes 8JWZ and 8JWY, respectively.

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Acknowledgement

This work was supported by the National Key Research and Development Program of China (2018YFA0507001), the Basic Research Program of Science and Technology Commission of Shanghai Municipality (21JC1402400), the National Natural Science Foundation of China (32171215, 81972828, 82172644, 82273857 and 81830083), and the National Key Scientific Infrastructure for Translational Medicine (Shanghai) (TMSK-2021-120). We thank the Instruments Sharing Platform of the School of Life Sciences, East China Normal University. We also thank the support of ECNU Multifunctional Platform for Innovation (001) and the National Super Computing Center in Zhengzhou for providing computational resources for this study. The synchrotron radiation experiments were performed at the BL45XU of Spring-8, Japan.

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Authors and Affiliations

  1. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China

    Yuan Weng, Xinyu Yang, Qiansen Zhang, Ying Chen, Yueming Xu, Huaiyu Yang, Mingyao Liu, Weiqiang Lu & Gaojie Song

  2. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China

    Chenyu Zhu, Qiong Xie & Yonghui Wang

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  1. Yuan Weng
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  2. Xinyu Yang
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Correspondence to Qiansen Zhang, Weiqiang Lu or Gaojie Song.

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Weng, Y., Yang, X., Zhang, Q. et al. Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A2 receptors. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-023-2459-8

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