8vf6
Crystal structure of Serine/threonine-protein kinase 33 (STK33) Kinase Domain in complex with inhibitor CDD-2211
Structural highlights
FunctionSTK33_HUMAN Serine/threonine protein kinase which phosphorylates VIME. May play a specific role in the dynamic behavior of the intermediate filament cytoskeleton by phosphorylation of VIME (By similarity). Not essential for the survival of KRAS-dependent AML cell lines.[1] Publication Abstract from PubMedMen or mice with homozygous serine/threonine kinase 33 (STK33) mutations are sterile owing to defective sperm morphology and motility. To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability. In mice, CDD-2807 exhibited no toxicity, efficiently crossed the blood-testis barrier, did not accumulate in brain, and induced a reversible contraceptive effect that phenocopied genetic STK33 perturbations without altering testis size. Thus, STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound. Reversible male contraception by targeted inhibition of serine/threonine kinase 33.,Ku AF, Sharma KL, Ta HM, Sutton CM, Bohren KM, Wang Y, Chamakuri S, Chen R, Hakenjos JM, Jimmidi R, Kent K, Li F, Li JY, Ma L, Madasu C, Palaniappan M, Palmer SS, Qin X, Robers MB, Sankaran B, Tan Z, Vasquez YM, Wang J, Wilkinson J, Yu Z, Ye Q, Young DW, Teng M, Kim C, Matzuk MM Science. 2024 May 24;384(6698):885-890. doi: 10.1126/science.adl2688. Epub 2024 , May 23. PMID:38781365[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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