4.7 Article

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

期刊

PLANT AND CELL PHYSIOLOGY
卷 63, 期 11, 页码 1720-1728

出版社

OXFORD UNIV PRESS
DOI: 10.1093/pcp/pcac127

关键词

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

资金

  1. Japan Society for the Promotion of Science [20K21272, 21H05656]
  2. Takeda Science Foundation
  3. World Premier International Research Center Initiative, Japan
  4. Graduate Program of Transformative ChemBio Research
  5. Nagoya University Interdisciplinary Frontier Fellowship - JST
  6. Science Research on Innovative Areas [18H04428, 20H05411]
  7. Nagoya University

向作者/读者索取更多资源

The circadian clock, an internal time-keeping system, coordinates physiological processes. BML-259, a small molecule with CDK5/CDK2 inhibition activity, lengthens Arabidopsis circadian clock periods.
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.

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