9P74
Crystal Structure of cGMP-dependent protein kinase from Plasmodium vivax in complex with inhibitor RUBP-61
This is a non-PDB format compatible entry.
Summary for 9P74
| Entry DOI | 10.2210/pdb9p74/pdb |
| Descriptor | cGMP-dependent protein kinase, GLYCEROL, BROMIDE ION, ... (6 entities in total) |
| Functional Keywords | ssgcid, structural genomics, seattle structural genomics center for infectious disease, cgmp-dependent protein kinase, plasmodium vivax, transferase |
| Biological source | Plasmodium vivax Sal-1 |
| Total number of polymer chains | 1 |
| Total formula weight | 100046.93 |
| Authors | Seattle Structural Genomics Center for Infectious Disease,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2025-06-20, release date: 2026-08-12) |
| Primary citation | Dhiyebi, H.,Mbaye, A.,Thaniana, A.,Gilleran, J.,Eck, T.,Ashraf, K.,Kudyba, K.,Fan, H.,Seibold, S.,Battaile, K.P.,Siekierka, J.,Johnson, E.,Roth, A.,De Rocher, A.,Lovell, S.,Miller, E.B.,Roberge, J.Y.,Bhanot, P. An orally available PfPKG inhibitor blocks Plasmodium's infection of the liver. Plos Pathog., 22:e1014322-e1014322, 2026 Cited by PubMed Abstract: Malaria remains a global health threat exacerbated by emerging resistance to antimalarial therapies and insecticides, climate-driven outbreaks, and limited chemoprotective options. Here, we report the characterization of RUPB-61, the first orally bioavailable inhibitor of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG). RUPB-61 prevents infection by P. falciparum and P. cynomolgi sporozoites, including the formation of hypnozoites by the latter. A single oral dose blocks liver infection by P. berghei sporozoites in vivo, demonstrating efficacy consistent with further development as a once-weekly prophylaxis based on pharmacokinetic modeling. The compound retains activity against field isolates resistant to chloroquine, mefloquine, cycloguanil, sulfadoxine and pyrimethamine, suggesting low likelihood of cross-resistance to existing antimalarials. Structural studies and free energy-based modeling guided-compound design prospectively validated the predictive accuracy of an in silico model of PfPKG interactions with this chemotype. While selectivity profiling identified off-target activity against human kinases, structural modeling provides a clear path for optimization. These results establish PfPKG inhibitors as promising candidates for chemoprevention and support further preclinical development of the RUPB-61 chemotype. PubMed: 42531257DOI: 10.1371/journal.ppat.1014322 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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