9NZK

Crystal structure of Yck2 with LY364947

Summary for 9NZK

• Entry DOI: 10.2210/pdb9nzk/pdb
• Descriptor: non-specific serine/threonine protein kinase, 4-(3-PYRIDIN-2-YL-1H-PYRAZOL-4-YL)QUINOLINE, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: yck2, kinase, kinase inhibitor, structural genomics, niaid, national institute of allergy and infectious diseases, center for structural biology of infectious diseases, csbid, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Candida albicans
• Total number of polymer chains: 1
• Total formula weight: 35740.46

Authors

Stogios, P.J.,Shirley, D.,Cowen, L.E.,Willson, T.,Savchenko, A.,Joachimiak, A.,Satchell, K.J.F.,Center for Structural Biology of Infectious Diseases (CSBID) (deposition date: 2025-04-01, release date: 2025-10-08, Last modification date: 2026-02-25)

Primary citation

Shirley, D.J.,Yiu, B.,Mancera-Ortiz, I.,Stogios, P.J.,Liu, Z.,Robbins, N.,Whitesell, L.,Cowen, L.E.,Drewry, D.H.,Willson, T.M.
Structure-activity Relationship for Diarylpyrazoles as Inhibitors of the Fungal Kinase Yck2.
Biorxiv, 2025

PubMed Abstract: Candida albicans is a growing global health threat, causing 1.5 million invasive infections and 1 million deaths annually. Yeast casein kinase 2 (Yck2) in has emerged as an antifungal target of the kinase inhibitor LY364947 (). Herein, we report Yck2 structure-activity relationships for 3,4- and 3,4,5-substituted pyrazole analogs of . X-ray crystallography and in vitro profiling revealed the importance of the hinge-binding heterocycle for Yck2 inhibition and fungal kinome selectivity. A hydrogen-bond network between the inhibitor, a bound water molecule, and catalytic residues within the ATP pocket was identified as a key determinant of selectivity over other fungal and human kinases. Phenol analog showed remarkable selectivity for Yck2 and Yck22 over all other protein kinases. Several of the analogs, including , demonstrated improved antifungal activity. These findings provide a framework for translating human kinase inhibitors into highly selective antifungal Yck2 inhibitors.

PubMed: 40672256
DOI: 10.1101/2025.07.12.664496

Experimental method

X-RAY DIFFRACTION (1.7 Å)