Crystal structure of the motor domain of centromere‐associated protein E in complex with a non‐hydrolysable ATP analogue

• Published in: FEBS letters 2023-04, Vol.597 (8), p.1138-1148
• Main Authors: Shibuya, Asuka, Suzuki, Akira, Ogo, Naohisa, Sawada, Jun‐ichi, Asai, Akira, Yokoyama, Hideshi
• Format: Article
• Language: English
• Subjects: Adenylyl Imidodiphosphate - analysis; Adenylyl Imidodiphosphate - metabolism; adenylyl‐imidodiphosphate; Antineoplastic Agents - pharmacology; Centromere - metabolism; centromere‐associated protein E; crystal structure; hydrolysis; kinesin; Microtubules - metabolism; Mitosis; neck linker
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.14602

Centromere‐associated protein E (CENP‐E) is a kinesin motor protein essential for mitosis and a new target for anticancer agents with less side effects. To rationally design anticancer drug candidates based on structure, it is important to determine the three‐dimensional structure of the CENP‐E motor domain bound to its inhibitor. Here, we report the first crystal structure of the CENP‐E motor domain in complex with a non‐hydrolysable ATP analogue, adenylyl‐imidodiphosphate (AMPPNP). Furthermore, the structure is compared with the ADP‐bound form of the CENP‐E motor domain as well as the AMPPNP‐bound forms of other kinesins. This study indicates that helix α4 of CENP‐E participates in the slow binding of CENP‐E to microtubules. These results will contribute to the development of anticancer drugs targeting CENP‐E. Centromere‐associated protein E (CENP‐E) is a kinesin motor protein essential for mitosis. Here, we report the first crystal structure of the CENP‐E motor domain in complex with a non‐hydrolysable ATP analogue, adenylyl‐imidodiphosphate (AMPPNP). Furthermore, the structure is compared with the ADP‐bound form of the CENP‐E motor domain as well as the AMPPNP‐bound forms of other kinesins.