A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude.
ARNTL Transcription Factors
/ metabolism
Animals
Binding Sites
CLOCK Proteins
/ metabolism
Cell Line, Tumor
Cell Nucleus
/ drug effects
Cell Survival
/ drug effects
Circadian Rhythm
/ drug effects
HEK293 Cells
Humans
Liver
/ drug effects
Male
Mice, Inbred C57BL
Models, Biological
Molecular Docking Simulation
Molecular Dynamics Simulation
Protein Binding
/ drug effects
Protein Transport
/ drug effects
Small Molecule Libraries
/ pharmacology
Subcellular Fractions
/ metabolism
Time Factors
brain and muscle Arnt-like protein-1 (BMAL1)
circadian clock
circadian locomotor output cycles kaput (CLOCK)
circadian regulation
circadian rhythm amplitude
drug design
drug development
gene expression
gene regulation
protein expression
transcription
transcription coregulator
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
13 03 2020
13 03 2020
Historique:
received:
02
10
2019
revised:
28
01
2020
pubmed:
6
2
2020
medline:
15
12
2020
entrez:
6
2
2020
Statut:
ppublish
Résumé
Proper function of many physiological processes requires a robust circadian clock. Disruptions of the circadian clock can result in metabolic diseases, mood disorders, and accelerated aging. Therefore, identifying small molecules that specifically modulate regulatory core clock proteins may potentially enable better management of these disorders. In this study, we applied a structure-based molecular-docking approach to find small molecules that specifically bind to the core circadian regulator, the transcription factor circadian locomotor output cycles kaput (CLOCK). We identified 100 candidate molecules by virtual screening of ∼2 million small molecules for those predicted to bind closely to the interface in CLOCK that interacts with its transcriptional co-regulator, Brain and muscle Arnt-like protein-1 (BMAL1). Using a mammalian two-hybrid system, real-time monitoring of circadian rhythm in U2OS cells, and various biochemical assays, we tested these compounds experimentally and found one, named CLK8, that specifically bound to and interfered with CLOCK activity. We show that CLK8 disrupts the interaction between CLOCK and BMAL1 and interferes with nuclear translocation of CLOCK both
Identifiants
pubmed: 32019867
pii: S0021-9258(17)48623-6
doi: 10.1074/jbc.RA119.011332
pmc: PMC7076206
pii:
doi:
Substances chimiques
ARNTL Transcription Factors
0
Small Molecule Libraries
0
CLOCK Proteins
EC 2.3.1.48
Banques de données
PDB
['4F3L']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3518-3531Informations de copyright
© 2020 Doruk et al.
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