9HW6
Toxoplasma gondii GSK3b bound to LY2090314 and disulphide bonded through the C223 residue
This is a non-PDB format compatible entry.
Summary for 9HW6
| Entry DOI | 10.2210/pdb9hw6/pdb |
| Related | 9HVX |
| Descriptor | Putative cell-cycle-associated protein kinase GSK, LY-2090314, PHOSPHATE ION, ... (4 entities in total) |
| Functional Keywords | gsk3b cell signalling kinase, transferase |
| Biological source | Toxoplasma gondii RH More |
| Total number of polymer chains | 4 |
| Total formula weight | 173019.54 |
| Authors | Swale, C.,Diaz-Martin, S.,Bowler, M.W. (deposition date: 2025-01-03, release date: 2025-10-22, Last modification date: 2025-12-03) |
| Primary citation | Diaz-Martin, S.,Swale, C.,Bellini, V.,Dobrescu, I.,Wenker, J.,Brenier-Pinchart, M.P.,Braun, L.,Tollec, A.,Corrao, C.,Coute, Y.,Mas, C.,Laurent, F.,Bowler, M.,Hakimi, M.A.,Bougdour, A. Structural and functional characterization of TgGSK3, a druggable kinase in Toxoplasma gondii. Nat Commun, 16:9765-9765, 2025 Cited by PubMed Abstract: Toxoplasma gondii and Cryptosporidium species are apicomplexan parasites of significant medical and veterinary importance. Although current therapeutic options for toxoplasmosis and cryptosporidiosis demonstrate notable efficacy, their clinical efficacy is often limited by suboptimal efficacy and frequent adverse effects. Moreover, therapeutic alternatives remain limited or nonexistent, particularly for cryptosporidiosis, for which nitazoxanide is currently the only approved medication to treat diarrhea in adults and children older than 1 year of age. To identify alternative therapeutic options for addressing these health challenges, we performed a phenotypic screening of an FDA-approved drug repurposing library against Toxoplasma. This screening identifies LY2090314 as a potent inhibitor of T. gondii and Cryptosporidium growth in mammalian cells. Through a target deconvolution strategy combining forward genetics, transcriptome sequencing, and computational mutation analysis, we elucidate the parasiticidal mechanism of LY2090314 and demonstrate that TgGSK3 kinase is its primary molecular target. We also report the first X-ray crystal structure of LY2090314 bound to TgGSK3, resolved at 2.1 Å, which reveals an interaction mode characteristic of type I ATP-competitive inhibitors. Furthermore, interactome analysis uncovers functional connections between TgGSK3 and key cytoskeletal and signaling regulators, providing insights into compound's effects. Collectively, these findings validate TgGSK3 as a promising therapeutic target for toxoplasmosis and offer mechanistic insights into apicomplexan GSK3 biology. PubMed: 41193440DOI: 10.1038/s41467-025-64701-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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