2. Academic Validation
  3. An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals

An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals

  • Cell Chem Biol. 2020 Sep 17;27(9):1192-1198.e5. doi: 10.1016/j.chembiol.2020.05.008.
Simon Miller 1,  Yoshiki Aikawa 1,  Akiko Sugiyama 1,  Yoshiko Nagai 1,  Aya Hara 1,  Tsuyoshi Oshima 2,  Kazuma Amaike 2,  Steve A Kay 3,  Kenichiro Itami 2,  Tsuyoshi Hirota 4
Affiliations

Affiliations

  • 1 Institute of Transformative Bio-Molecules, Nagoya University, Nagoya 464-8601, Japan.
  • 2 Institute of Transformative Bio-Molecules, Nagoya University, Nagoya 464-8601, Japan; Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya 464-8601, Japan.
  • 3 Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
  • 4 Institute of Transformative Bio-Molecules, Nagoya University, Nagoya 464-8601, Japan. Electronic address: [email protected].
PMID: 32502390 DOI: 10.1016/j.chembiol.2020.05.008
Abstract

Cryptochrome 1 (CRY1) and CRY2 are core regulators of the circadian clock, and the development of isoform-selective modulators is important for the elucidation of their redundant and distinct functions. Here, we report the identification and functional characterization of a small-molecule modulator of the mammalian circadian clock that selectively controls CRY1. Cell-based circadian chemical screening identified a thienopyrimidine derivative KL201 that lengthened the period of circadian rhythms in cells and tissues. Functional assays revealed stabilization of CRY1 but not CRY2 by KL201. A structure-activity relationship study of KL201 derivatives in combination with X-ray crystallography of the CRY1-KL201 complex uncovered critical sites and interactions required for CRY1 regulation. KL201 bound to CRY1 in overlap with FBXL3, a subunit of ubiquitin ligase complex, and the effect of KL201 was blunted by knockdown of FBXL3. KL201 will facilitate isoform-selective regulation of CRY1 to accelerate chronobiology research and therapeutics against clock-related diseases.

Keywords

X-ray crystallography; chemical biology; circadian clock; cryptochrome; small-molecule modulator.

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