Structure-Function Study of a Novel Inhibitor of Cyclin-Dependent Kinase C in Arabidopsis

Ami N. Saito, Akari E. Maeda, Tomoaki T. Takahara, Hiromi Matsuo, Michiya Nishina, Azusa Ono, Katsuhiro Shiratake, Michitaka Notaguchi, Takeshi Yanai, Toshinori Kinoshita, Eisuke Ota, Kazuhiro J. Fujimoto, Junichiro Yamaguchi, Norihito Nakamichi

Research output: Contribution to journalArticlepeer-review


The circadian clock, an internal time-keeping system with a period of about 24 h, coordinates many physiological processes with the day-night cycle. We previously demonstrated that BML-259 [N-(5-isopropyl-2-thiazolyl) phenylacetamide], a small molecule with mammal CYCLIN DEPENDENT KINASE 5 (CDK5)/CDK2 inhibition activity, lengthens Arabidopsis thaliana (Arabidopsis) circadian clock periods. BML-259 inhibits Arabidopsis CDKC kinase, which phosphorylates RNA polymerase II in the general transcriptional machinery. To accelerate our understanding of the inhibitory mechanism of BML-259 on CDKC, we performed structure-function studies of BML-259 using circadian period-lengthening activity as an estimation of CDKC inhibitor activity in vivo. The presence of a thiazole ring is essential for period-lengthening activity, whereas acetamide, isopropyl and phenyl groups can be modified without effect. BML-259 analog TT-539, a known mammal CDK5 inhibitor, did not lengthen the period nor did it inhibit Pol II phosphorylation. TT-361, an analog having a thiophenyl ring instead of a phenyl ring, possesses stronger period-lengthening activity and CDKC;2 inhibitory activity than BML-259. In silico ensemble docking calculations using Arabidopsis CDKC;2 obtained by a homology modeling indicated that the different binding conformations between these molecules and CDKC;2 explain the divergent activities of TT539 and TT361.

Original languageEnglish
Pages (from-to)1720-1728
Number of pages9
JournalPlant & cell physiology
Issue number11
Publication statusPublished - 2022 Nov 22


  • Arabidopsis thaliana (Arabidopsis)
  • CDKC;2
  • Circadian clock
  • In silico study
  • Structure–activity relationship

ASJC Scopus subject areas

  • Physiology
  • Plant Science
  • Cell Biology


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