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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


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 and Cell Physiology
Issue number11
Publication statusPublished - 2022 Nov 1


  • 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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