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.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Miller S,Aikawa Y,Sugiyama A,Nagai Y,Hara A,Oshima T,Amaike K,Kay SA,Itami K,Hirota Tdoi
10.1016/j.chembiol.2020.05.008subject
Has Abstractpub_date
2020-09-17 00:00:00pages
1192-1198.e5issue
9eissn
2451-9456issn
2451-9448pii
S2451-9456(20)30185-9journal_volume
27pub_type
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