8VF6

Crystal structure of Serine/threonine-protein kinase 33 (STK33) Kinase Domain in complex with inhibitor CDD-2211

これはPDB形式変換不可エントリーです。

8VF6 の概要

• エントリーDOI: 10.2210/pdb8vf6/pdb
• 分子名称: Serine/threonine-protein kinase 33, {3-[([1,1'-biphenyl]-2-yl)ethynyl]-1H-indazol-5-yl}[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methanone (3 entities in total)
• 機能のキーワード: kinase, stk33, cytosolic protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65938.19

構造登録者

Ta, H.M.,Kim, C.,Ku, K.A.,Matzuk, M.M. (登録日: 2023-12-21, 公開日: 2024-06-05)

主引用文献

Ku, A.F.,Sharma, K.L.,Ta, H.M.,Sutton, C.M.,Bohren, K.M.,Wang, Y.,Chamakuri, S.,Chen, R.,Hakenjos, J.M.,Jimmidi, R.,Kent, K.,Li, F.,Li, J.Y.,Ma, L.,Madasu, C.,Palaniappan, M.,Palmer, S.S.,Qin, X.,Robers, M.B.,Sankaran, B.,Tan, Z.,Vasquez, Y.M.,Wang, J.,Wilkinson, J.,Yu, Z.,Ye, Q.,Young, D.W.,Teng, M.,Kim, C.,Matzuk, M.M.
Reversible male contraception by targeted inhibition of serine/threonine kinase 33.
Science, 384:885-890, 2024

PubMed Abstract: Men or mice with homozygous serine/threonine kinase 33 () 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 perturbations without altering testis size. Thus, STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound.

PubMed: 38781365
DOI: 10.1126/science.adl2688

実験手法

X-RAY DIFFRACTION (2.7 Å)