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Science 337 (6091): 189-194

Copyright © 2012 by the American Association for the Advancement of Science

Crystal Structure of the Heterodimeric CLOCK:BMAL1 Transcriptional Activator Complex

Nian Huang,1,* Yogarany Chelliah,2,3,* Yongli Shan,2 Clinton A. Taylor,1,4 Seung-Hee Yoo,2 Carrie Partch,1,2,3,{dagger} Carla B. Green,2 Hong Zhang,1,{ddagger} Joseph S. Takahashi2,3,{ddagger}

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.

1 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4 Molecular Biophysics Graduate Program, Division of Basic Science, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

* These authors contributed equally to this work.

{dagger} Present address: Chemistry and Biochemistry Department, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.

{ddagger} To whom correspondence should be addressed. E-mail: joseph.takahashi{at}utsouthwestern.edu (J.S.T.); zhang{at}chop.swmed.edu (H.Z.)

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