6U69
Crystal structure of Yck2 from Candida albicans, apoenzyme
Summary for 6U69
| Entry DOI | 10.2210/pdb6u69/pdb |
| Descriptor | Serine/threonine protein kinase, SULFATE ION, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | casein kinase 1, yck2, kinase, structural genomics, center for structural genomics of infectious diseases, niaid, national institute of allergy and infectious diseases, csgid, transferase |
| Biological source | Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast) |
| Total number of polymer chains | 1 |
| Total formula weight | 35620.86 |
| Authors | Stogios, P.J.,Evdokimova, E.,Di Leo, R.,Savchenko, A.,Joachimiak, A.,Satchell, K.J.F.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2019-08-29, release date: 2019-10-09, Last modification date: 2023-10-11) |
| Primary citation | Caplan, T.,Lorente-Macias, A.,Stogios, P.J.,Evdokimova, E.,Hyde, S.,Wellington, M.A.,Liston, S.,Iyer, K.R.,Puumala, E.,Shekhar-Guturja, T.,Robbins, N.,Savchenko, A.,Krysan, D.J.,Whitesell, L.,Zuercher, W.J.,Cowen, L.E. Overcoming Fungal Echinocandin Resistance through Inhibition of the Non-essential Stress Kinase Yck2. Cell Chem Biol, 27:269-282.e5, 2020 Cited by PubMed Abstract: New strategies are urgently needed to counter the threat to human health posed by drug-resistant fungi. To explore an as-yet unexploited target space for antifungals, we screened a library of protein kinase inhibitors for the ability to reverse resistance of the most common human fungal pathogen, Candida albicans, to caspofungin, a widely used antifungal. This screen identified multiple 2,3-aryl-pyrazolopyridine scaffold compounds capable of restoring caspofungin sensitivity. Using chemical genomic, biochemical, and structural approaches, we established the target for our most potent compound as Yck2, a casein kinase 1 family member. Combination of this compound with caspofungin eradicated drug-resistant C. albicans infection while sparing co-cultured human cells. In mice, genetic depletion of YCK2 caused an ∼3-log decline in fungal burden in a model of systemic caspofungin-resistant C. albicans infection. Structural insights and our tool compound's profile in culture support targeting the Yck2 kinase function as a broadly active antifungal strategy. PubMed: 31924499DOI: 10.1016/j.chembiol.2019.12.008 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.61 Å) |
Structure validation
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