Binding of the Origin Recognition Complex (ORC) to origins of replication marks the first step in the initiation of replication 4 Casters of the genome in all eukaryotic cells.Here, we report the structure of the active form of human ORC determined by X-ray crystallography and cryo-electron microscopy.The complex is composed of an ORC1/4/5 motor module lobe in an organization reminiscent of the DNA polymerase clamp loader complexes.A second lobe contains the ORC2/3 subunits.
The complex is organized as a double-layered shallow corkscrew, with the AAA+ and AAA+-like domains forming one layer, and the winged-helix domains (WHDs) forming a top layer.CDC6 fits easily between ORC1 and ORC2, completing the ring and the DNA-binding channel, forming an additional ATP hydrolysis site.Analysis of the ATPase activity of the complex provides a basis MORNING RISE for understanding ORC activity as well as molecular defects observed in Meier-Gorlin Syndrome mutations.