6LUE

Crystal structure of mouse Cryptochrome 1 in complex with compound KL201

6LUE の概要

• エントリーDOI: 10.2210/pdb6lue/pdb
• 分子名称: Cryptochrome-1, 2-bromanyl-N-(5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-4-yl)benzamide (3 entities in total)
• 機能のキーワード: cryptochrome, cry, circadian clock, kl201, circadian clock protein
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 115520.03

構造登録者

Miller, S.,Aikawa, Y.,Hirota, T. (登録日: 2020-01-27, 公開日: 2020-06-10, 最終更新日: 2023-11-29)

主引用文献

Miller, S.,Aikawa, Y.,Sugiyama, A.,Nagai, Y.,Hara, A.,Oshima, T.,Amaike, K.,Kay, S.A.,Itami, K.,Hirota, T.
An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals.
Cell Chem Biol, 27:1192-1198.e5, 2020

PubMed 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.

PubMed: 32502390
DOI: 10.1016/j.chembiol.2020.05.008

実験手法

X-RAY DIFFRACTION (2.1 Å)