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<p>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 (AlF<sub>4</sub><sup>-</sup> 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.</p>

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Comprehensive profiling of the catalytic conformations of human Guanylate kinase

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月25日

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  • 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,
  • Ke Ruan

摘要

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.