Comprehensive profiling of the catalytic conformations of human Guanylate kinase

Lei Wang, Zihuan Li, Yumi Xuan, Jingkun Qin, Shuju Li, Fumei Zhong, Yuexiao Song, Kanglong Yang, Mengqi Lv, Fudong Li, Zhang Jiahai, Yueyin Pan, Shouhong Guang, Yuzheng Zhao, Yunyu Shi, Xing Liu (), Yingying Du (), Jia Gao () and Ke Ruan ()
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Lei Wang: University of Science and Technology of China
Zihuan Li: University of Science and Technology of China
Yumi Xuan: University of Science and Technology of China
Jingkun Qin: University of Science and Technology of China
Shuju Li: University of Science and Technology of China
Fumei Zhong: University of Science and Technology of China
Yuexiao Song: the First Affiliated Hospital of Anhui Medical University
Kanglong Yang: University of Science and Technology of China
Mengqi Lv: University of Science and Technology of China
Fudong Li: University of Science and Technology of China
Zhang Jiahai: University of Science and Technology of China
Yueyin Pan: The First Affiliated Hospital of USTC
Shouhong Guang: University of Science and Technology of China
Yuzheng Zhao: East China University of Science and Technology
Yunyu Shi: University of Science and Technology of China
Xing Liu: University of Science and Technology of China
Yingying Du: the First Affiliated Hospital of Anhui Medical University
Jia Gao: University of Science and Technology of China
Ke Ruan: University of Science and Technology of China

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Human guanylate kinase (GMPK) as the sole enzyme for GDP biosynthesis plays pivotal roles in antiviral prodrug activation and tumorigenesis. Despite its biological significance, the catalytic mechanism remains poorly understood. Here, we resolve crystal structures of GMPK in free and GMP-bound form, revealing the interdomain motions of GMPBD and LID relative to the CORE domain. Biochemical assays demonstrate potassium’s dual functionality in substrate recognition and phosphoryl transfer catalysis. Structural analyses uncover intradomain conformational motion within the LID domain and essential interactions for ADP/ATP binding. Notably, the cooperative ATPγS binding potentiated by prior GMP binding are structurally elucidated. Three key complexes, pre-reaction state (GMP/ATPγS), transition state (AlF4- mimic), and post-reaction state (GDP/ADP), collectively delineate the reversible catalytic pathway. This comprehensive structural characterization of GMPK’s dynamic landscape establishes a foundation for developing conformation-specific inhibitors through structure-guided drug design.

Date: 2025
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DOI: 10.1038/s41467-025-61732-y

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