Conformational control and DNA-binding mechanism of the metazoan origin recognition complex

The onset of chromosomal DNA replication relies on dedicated initiator proteins to chaperone ring-shaped helicases onto DNA. In most eukaryotes, initiators are multisubunit protein complexes that require ATP to bind DNA and to aid helicase recruitment and loading. Although structural studies have recently elucidated high-resolution views of the initiator in isolation or in helicase-containing loading intermediates, how the eukaryotic initiator itself associates with DNA and how these interactions are regulated by conformational changes are not well understood. We use a combination of biochemical and structural studies of the Drosophila initiator origin recognition complex (ORC) to show that conformational alterations in metazoan ORC help regulate its DNA-binding activity, and that ORC, together with its cofactor Cdc6, bends substrate DNA prior to helicase loading.