2X7E

Crystal structure of human kinesin Eg5 in complex with (R)-fluorastrol

2X7E の概要

• エントリーDOI: 10.2210/pdb2x7e/pdb
• 関連するPDBエントリー: 1II6 1Q0B 1X88 1YRS 2FKY 2FL2 2FL6 2G1Q 2GM1 2UYI 2UYM 2WOG 2X2R 2X7C 2X7D
• 分子名称: KINESIN-LIKE PROTEIN KIF11, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: microtubule, atp-binding, motor protein, cell division, mitosis, inhibitor, cell cycle, nucleotide-binding, ksp
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm: P52732
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 83767.02

構造登録者

Kaan, H.Y.K.,Ulaganathan, V.,Rath, O.,Laggner, C.,Prokopcova, H.,Dallinger, D.,Kappe, C.O.,Kozielski, F. (登録日: 2010-02-26, 公開日: 2010-07-14, 最終更新日: 2023-12-20)

主引用文献

Kaan, H.Y.K.,Ulaganathan, V.,Rath, O.,Prokopcova, H.,Dallinger, D.,Kappe, C.O.,Kozielski, F.
Structural Basis for Inhibition of Eg5 by Dihydropyrimidines: Stereoselectivity of Antimitotic Inhibitors Enastron, Dimethylenastron and Fluorastrol.
J.Med.Chem., 53:5676-, 2010

PubMed Abstract: Human kinesin Eg5, which plays an essential role in mitosis by establishing the bipolar spindle, has proven to be an interesting drug target for the development of cancer chemotherapeutics. Here, we report the crystal structures of the Eg5 motor domain complexed with enastron, dimethylenastron, and fluorastrol. By comparing these structures to that of monastrol and mon-97, we identified the main reasons for increased potency of these new inhibitors, namely the better fit of the ligand to the allosteric binding site and the addition of fluorine atoms. We also noticed preferential binding of the S-enantiomer of enastron and dimethylenastron to Eg5, while the R-enantiomer of fluorastrol binds preferentially to Eg5. In addition, we performed a multidrug resistance (MDR) study in cell lines overexpressing P-glycoprotein (Pgp). We showed that one of these inhibitors may have the potential to overcome susceptibility to this efflux pump and hence overcome common resistance associated with tubulin-targeting drugs.

PubMed: 20597485
DOI: 10.1021/JM100421N

実験手法

X-RAY DIFFRACTION (2.4 Å)