Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 24, Issue 3, Pages 316-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3372
Keywords
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Funding
- NIH [P41 GM103310]
- US National Institutes of Health [GM111742, GM45436]
- Biotechnology and Biological Sciences Research Council UK [P56061]
- Wellcome Trust [P56628, 103139, 092076, 108504]
- Wellcome Trust [107903/Z/15/Z] Funding Source: Wellcome Trust
- BBSRC [BB/N000323/1] Funding Source: UKRI
- MRC [MC_U120085811] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/N000323/1] Funding Source: researchfish
- Medical Research Council [1583051, MC_U120085811] Funding Source: researchfish
- Wellcome Trust [107903/Z/15/Z] Funding Source: researchfish
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To initiate DNA replication, the origin recognition complex (ORC) and Cdc6 load an Mcm2-7 double hexamer onto DNA. Without ATP hydrolysis, ORC-Cdc6 recruits one Cdt1-bound Mcm2-7 hexamer, thus forming an ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) helicase-loading intermediate. Here we report a 3.9-angstrom structure of Saccharomyces cerevisiae OCCM on DNA. Flexible Mcm2-7 winged-helix domains (WHDs) engage ORC-Cdc6. A three-domain Cdt1 configuration embraces Mcm2, Mcm4, and Mcm6, thus comprising nearly half of the hexamer. The Cdt1 C-terminal domain extends to the Mcm6 WHD, which binds the Orc4 WHD. DNA passes through the ORC-Cdc6 and Mcm2-7 rings. Origin DNA interaction is mediated by an a-helix within Orc4 and positively charged loops within Orc2 and Cdc6. The Mcm2-7 C-tier AAA+ ring is topologically closed by an Mcm5 loop that embraces Mcm2, but the N-tier-ring Mcm2-Mcm5 interface remains open. This structure suggests a loading mechanism of the first Cdt1-bound Mcm2-7 hexamer by ORC-Cdc6.
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