TY - JOUR TI - Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex AU - Nangle, Shannon N AU - Rosensweig, Clark AU - Koike, Nobuya AU - Tei, Hajime AU - Takahashi, Joseph S AU - Green, Carla B AU - Zheng, Ning A2 - Ptáček, Louis VL - 3 PY - 2014 DA - 2014/08/15 SP - e03674 C1 - eLife 2014;3:e03674 DO - 10.7554/eLife.03674 UR - https://doi.org/10.7554/eLife.03674 AB - The mammalian circadian clock is driven by a transcriptional–translational feedback loop, which produces robust 24-hr rhythms. Proper oscillation of the clock depends on the complex formation and periodic turnover of the Period and Cryptochrome proteins, which together inhibit their own transcriptional activator complex, CLOCK-BMAL1. We determined the crystal structure of the CRY-binding domain (CBD) of PER2 in complex with CRY2 at 2.8 Å resolution. PER2-CBD adopts a highly extended conformation, embracing CRY2 with a sinuous binding mode. Its N-terminal end tucks into CRY adjacent to a large pocket critical for CLOCK-BMAL1 binding, while its C-terminal half flanks the CRY2 C-terminal helix and sterically hinders the recognition of CRY2 by the FBXL3 ubiquitin ligase. Unexpectedly, a strictly conserved intermolecular zinc finger, whose integrity is important for clock rhythmicity, further stabilizes the complex. Our structure-guided analyses show that these interspersed CRY-interacting regions represent multiple functional modules of PERs at the CRY-binding interface. KW - circadian rhythm KW - cryptochrome KW - period JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -