Structure and comparison of the motor domain of centromere‐associated protein E

Centromere‐associated protein E (CENP‐E) plays an essential role in mitosis and is a target candidate for anticancer drugs. However, it is difficult to design small‐molecule inhibitors of CENP‐E kinesin motor ATPase activity owing to a lack of structural information on the CENP‐E motor domain in com...

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Bibliographic Details
Published in:Acta crystallographica. Section D, Biological crystallography. Biological crystallography., 2021-03, Vol.77 (3), p.280-287
Main Authors: Shibuya, Asuka, Ogo, Naohisa, Sawada, Jun-ichi, Asai, Akira, Yokoyama, Hideshi
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Adenosine triphosphate
anticancer drugs
Antineoplastic drugs
Antitumor agents
Binding sites
Cancer
CENP‐E
Crystal structure
Crystallization
Drug delivery
Drug development
Drugs
Inhibitors
Kinesin
kinesins
Mitosis
Nucleotides
Proteins
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Summary:Centromere‐associated protein E (CENP‐E) plays an essential role in mitosis and is a target candidate for anticancer drugs. However, it is difficult to design small‐molecule inhibitors of CENP‐E kinesin motor ATPase activity owing to a lack of structural information on the CENP‐E motor domain in complex with its inhibitors. Here, the CENP‐E motor domain was crystallized in the presence of an ATP‐competitive inhibitor and the crystal structure was determined at 1.9 Å resolution. In the determined structure, ADP was observed instead of the inhibitor in the nucleotide‐binding site, even though no ADP was added during protein preparation. Structural comparison with the structures of previously reported CENP‐E and those of other kinesins indicates that the determined structure is nearly identical except for several loop regions. However, the retention of ADP in the nucleotide‐binding site of the structure strengthens the biochemical view that the release of ADP is a rate‐limiting step in the ATPase cycle of CENP‐E. These results will contribute to the development of anticancer drugs targeting CENP‐E and to understanding the function of kinesin motor domains. Crystallization and structure determination of the motor domain of centromere‐associated protein E in complex with its inhibitor was performed. In the determined structure, endogenous ADP was observed in the nucleotide‐binding site instead of the inhibitor.
ISSN:2059-7983
0907-4449
2059-7983
1399-0047
DOI:10.1107/S2059798321000176