Journal
NATURE CHEMICAL BIOLOGY
Volume 16, Issue 6, Pages 676-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-0505-1
Keywords
-
Categories
Funding
- JST PRESTO Grant [JPMJPR14LA]
- JSPS [15H05590, 18H02402, 16H06174, 19H03266, 19K22693, 18K06316]
- Takeda Science Foundation
- Suzuken Memorial Foundation
- AMED Grant [JP19gm6110026]
- JST PRESTO Grant
- Uehara Memorial Foundation
- Sumitomo Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Cell Science Research Foundation
- MEXT PDIS Grant
- BINDS from AMED [JP19am0101074-0055, JP19am0101071-0529]
- Grants-in-Aid for Scientific Research [15H05590, 19K22693, 19H03266, 16H06174, 18H02402, 18K06316] Funding Source: KAKEN
Ask authors/readers for more resources
Cell-based phenotypic screening of small-molecule circadian clock modulators identified isoform-selective compounds for highly homologous clock proteins CRY1 and CRY2, revealing a key role of the disordered C-terminal region in compound selectivity. 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available