| Structural highlights
Function
[CRY1_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 PubMed
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.
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 Also
References
- ↑ Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell. 1999 Jul 23;98(2):193-205. PMID:10428031
- ↑ Kondratov RV, Kondratova AA, Lee C, Gorbacheva VY, Chernov MV, Antoch MP. Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES. Cell Cycle. 2006 Apr;5(8):890-5. Epub 2006 Apr 17. PMID:16628007
- ↑ Chaves I, Yagita K, Barnhoorn S, Okamura H, van der Horst GT, Tamanini F. Functional evolution of the photolyase/cryptochrome protein family: importance of the C terminus of mammalian CRY1 for circadian core oscillator performance. Mol Cell Biol. 2006 Mar;26(5):1743-53. PMID:16478995 doi:10.1128/MCB.26.5.1743-1753.2006
- ↑ Miller S, Aikawa Y, Sugiyama A, Nagai Y, Hara A, Oshima T, Amaike K, Kay SA, Itami K, Hirota T. An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals. Cell Chem Biol. 2020 Jun 1. pii: S2451-9456(20)30185-9. doi:, 10.1016/j.chembiol.2020.05.008. PMID:32502390 doi:http://dx.doi.org/10.1016/j.chembiol.2020.05.008
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