6lue
From Proteopedia
Crystal structure of mouse Cryptochrome 1 in complex with compound KL201
Structural highlights
FunctionCRY1_MOUSE Blue light-dependent regulator of the circadian feedback loop. Inhibits CLOCK|NPAS2-ARNTL E box-mediated transcription. Acts, in conjunction with CRY2, in maintaining period length and circadian rhythmicity. Has no photolyase activity. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. May inhibit CLOCK|NPAS2-ARNTL transcriptional activity through stabilizing the unphosphorylated form of ARNTL.[1] [2] [3] Publication Abstract from PubMedCryptochrome 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. An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals.,Miller S, Aikawa Y, Sugiyama A, Nagai Y, Hara A, Oshima T, Amaike K, Kay SA, Itami K, Hirota T Cell Chem Biol. 2020 Jun 1. pii: S2451-9456(20)30185-9. doi:, 10.1016/j.chembiol.2020.05.008. PMID:32502390[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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