1. National Creative Research Center for Structural Biology and Department of Life Science, Pohang University of Science and Technology, Hyo-ja dong, San31, Pohang, KyungBook, South Korea
2. Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-Ku, Senda, Miyagi 980-8578, Japan
3. Biomolecular and Technology Department, Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan
4. Bioscience Division, Structural Biology Center, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA
5. These authors contributed equally to the work.

Correspondence to: Yunje Cho¹ Correspondence and requests for materials should be addressed to Y.C. (Email: yunje@postech.ac.kr).
The coordinates and structure factors have been deposited in the Protein Data Bank (accession code 1WLQ).

Abstract

To maintain chromosome stability in eukaryotic cells, replication origins must be licensed by loading mini-chromosome maintenance (MCM2–7) complexes once and only once per cell cycle^{1, 2, 3, 4, 5, 6, 7, 8, 9}. This licensing control is achieved through the activities of geminin^{10, 11, 12} and cyclin-dependent kinases^{9, 13, 14}. Geminin binds tightly to Cdt1, an essential component of the replication licensing system^{6, 15, 16, 17, 18}, and prevents the inappropriate reinitiation of replication on an already fired origin. The inhibitory effect of geminin is thought to prevent the interaction between Cdt1 and the MCM helicase^{19, 20}. Here we describe the crystal structure of the mouse geminin–Cdt1 complex using tGeminin (residues 79–157, truncated geminin) and tCdt1 (residues 172–368, truncated Cdt1). The amino-terminal region of a coiled-coil dimer of tGeminin interacts with both N-terminal and carboxy-terminal parts of tCdt1. The primary interface relies on the steric complementarity between the tGeminin dimer and the hydrophobic face of the two short N-terminal helices of tCdt1 and, in particular, Pro 181, Ala 182, Tyr 183, Phe 186 and Leu 189. The crystal structure, in conjunction with our biochemical data, indicates that the N-terminal region of tGeminin might be required to anchor tCdt1, and the C-terminal region of tGeminin prevents access of the MCM complex to tCdt1 through steric hindrance.

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