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Science. 2012 Jul 13;337(6091):189-94. doi: 10.1126/science.1222804. Epub 2012 May 31.

Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex.

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  • 1Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Abstract

The circadian clock in mammals is driven by an autoregulatory transcriptional feedback mechanism that takes approximately 24 hours to complete. A key component of this mechanism is a heterodimeric transcriptional activator consisting of two basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) domain protein subunits, CLOCK and BMAL1. Here, we report the crystal structure of a complex containing the mouse CLOCK:BMAL1 bHLH-PAS domains at 2.3 Å resolution. The structure reveals an unusual asymmetric heterodimer with the three domains in each of the two subunits--bHLH, PAS-A, and PAS-B--tightly intertwined and involved in dimerization interactions, resulting in three distinct protein interfaces. Mutations that perturb the observed heterodimer interfaces affect the stability and activity of the CLOCK:BMAL1 complex as well as the periodicity of the circadian oscillator. The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock.

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PMID:
22653727
[PubMed - indexed for MEDLINE]
PMCID:
PMC3694778
Free PMC Article

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