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Isoform-selective regulation of mammalian cryptochromes.
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2020-03-30 , DOI: 10.1038/s41589-020-0505-1
Simon Miller 1 , You Lee Son 2 , Yoshiki Aikawa 1 , Eri Makino 1, 3 , Yoshiko Nagai 1 , Ashutosh Srivastava 1 , Tsuyoshi Oshima 1, 3 , Akiko Sugiyama 1 , Aya Hara 1 , Kazuhiro Abe 4 , Kunio Hirata 5 , Shinya Oishi 6 , Shinya Hagihara 1, 3 , Ayato Sato 1 , Florence Tama 1, 7, 8 , Kenichiro Itami 1, 3 , Steve A Kay 9 , Megumi Hatori 2 , Tsuyoshi Hirota 1
Affiliation  

CRY1 and CRY2 are essential components of the circadian clock controlling daily physiological rhythms. Accumulating evidences indicate distinct roles of these highly homologous proteins, in addition to redundant functions. Therefore, the development of isoform-selective compounds represents an effective approach towards understanding the similarities and differences of CRY1 and CRY2 by controlling each isoform individually. We conducted phenotypic screenings of circadian clock modulators, and identified KL101 and TH301 that selectively stabilize CRY1 and CRY2, respectively. Crystal structures of CRY-compound complexes revealed conservation of compound-binding sites between CRY1 and CRY2. We further discovered a unique mechanism underlying compound selectivity in which the disordered C-terminal region outside the pocket was required for the differential effects of KL101 and TH301 against CRY isoforms. By using these compounds, we found a new role of CRY1 and CRY2 as enhancers of brown adipocyte differentiation, providing the basis of CRY-mediated regulation of energy expenditure.

中文翻译:

哺乳动物隐色素的同工型选择性调节。

CRY1和CRY2是控制日常生理节律的生物钟的重要组成部分。越来越多的证据表明,这些高同源蛋白除了具有多余的功能外,还发挥着不同的作用。因此,开发同工型选择性化合物代表了一种通过分别控制每个同工型来理解CRY1和CRY2的异同的有效方法。我们进行了昼夜节律调节器的表型筛选,并确定了分别选择性稳定CRY1和CRY2的KL101和TH301。CRY化合物配合物的晶体结构揭示了CRY1和CRY2之间化合物结合位点的保守性。我们进一步发现了化合物选择性背后的独特机制,其中口袋外的无序C末端区域是KL101和TH301对CRY亚型的差异作用所必需的。通过使用这些化合物,我们发现了CRY1和CRY2作为棕色脂肪细胞分化增强剂的新作用,为CRY介导的能量消耗调节提供了基础。
更新日期:2020-04-24
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