Crystal structure of mammalian cryptochrome in complex with a small molecule competitor of its ubiquitin ligase
Dear Editor,
The cryptochrome (CRY) flavoproteins are critical components of the mammalian molecular circadian clock,which operates through an auto-regulatory transcription-translation feedback loop [1].In this clockwork,a pair of transcription factors,CLOCK and BMAL 1,drive the expression of CRYs,Periods (PERs),and other clock-controlled genes,while CRYs and PERs heterodimerize and repress their own gene expression by inhibiting CLOCK-BMALl-mediated transcription [2,3].To establish rhythmic protein oscillation,CRYs are ubiquitinated by the SCFFBXL3 ubiquitin ligase and targeted for rapid proteasomal degradation [4-6].
A recent cell-based screen of small-molecule circadian modulators identified three carbazole derivatives,which are characterized by their common dose-dependent circadian period-lengthening activity [7].Further analyses have shown that the representative compound,KL001,acts by directly interacting with CRYs and protecting them from SCFFBXL3-mediated ubiquitination.This pharmacological activity results in CRY stabilization,which lengthens the circadian period.
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the Howard Hughes Medical Institute;the National Institutes of HealthR01-CA107134 to NZ,and T32-GM007750 to SN
2014-01-23（万方平台首次上网日期，不代表论文的发表时间）
共3页
1417-1419
