9JAG

GMPK in complex with ADP

Summary for 9JAG

• Entry DOI: 10.2210/pdb9jag/pdb
• Descriptor: Guanylate kinase, SULFATE ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: guanylate kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 22975.50

Authors

Wang, L.,Ruan, K. (deposition date: 2024-08-24, release date: 2025-09-03, Last modification date: 2025-09-10)

Primary citation

Wang, L.,Li, Z.,Xuan, Y.,Qin, J.,Li, S.,Zhong, F.,Song, Y.,Yang, K.,Lv, M.,Li, F.,Jiahai, Z.,Pan, Y.,Guang, S.,Zhao, Y.,Shi, Y.,Liu, X.,Du, Y.,Gao, J.,Ruan, K.
Comprehensive profiling of the catalytic conformations of human Guanylate kinase.
Nat Commun, 16:6859-6859, 2025

PubMed 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 (AlF 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.

PubMed: 40715061
DOI: 10.1038/s41467-025-61732-y

Experimental method

X-RAY DIFFRACTION (1.9 Å)