Structure of the eukaryotic replicative CMG helicase and pumpjack motion

The CMG helicase is composed of Cdc45, Mcm2-7 and GINS. Here we report the structure of the S. cerevisiae CMG determined by cryo-EM at a resolution of 3.7–4.8 Å. The structure reveals that GINS and Cdc45 scaffold the N-tier of the helicase while enabling motion of the AAA+ C-tier. CMG exists in two alternating conformations, compact and extended, suggesting that the helicase functions like an inchworm. The N-terminal regions of the Mcm2-7, braced by Cdc45-GINS, form a rigid platform upon which the AAA+ C-domains make longitudinal motions, nodding up and down like an oil rig pumpjack makes nodding motions attached to a stable platform. The Mcm ring is remodeled in CMG relative to the inactive Mcm2-7 double-hexamer. The Mcm5 winged helix domain is inserted into the central channel, blocking entry of dsDNA, and supporting a steric exclusion DNA unwinding model.