2XAE

Crystal structure of human kinesin Eg5 in complex with (R)-2-amino-3-((S)-2-methyl-1,1-diphenylbutylthio)propanoic acid

2XAE の概要

• エントリーDOI: 10.2210/pdb2xae/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 2X7E
• 分子名称: KINESIN-LIKE PROTEIN KIF11, (2R)-2-AMINO-3-[(4-CHLOROPHENYL)-DIPHENYL-METHYL]SULFANYL-PROPANOIC ACID, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: cell cycle, mitosis, 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: 3
• 化学式量合計: 126038.66

構造登録者

Kaan, H.Y.K.,Weiss, J.,Menger, D.,Ulaganathan, V.,Tkocz, K.,Laggner, C.,Popowycz, F.,Joseph, B.,Kozielski, F. (登録日: 2010-03-31, 公開日: 2011-03-30, 最終更新日: 2023-12-20)

主引用文献

Kaan, H.Y.K.,Weiss, J.,Menger, D.,Ulaganathan, V.,Tkocz, K.,Laggner, C.,Popowycz, F.,Joseph, B.,Kozielski, F.
Structure-Activity Relationship and Multidrug Resistance Study of New S-Trityl-L-Cysteine Derivatives as Inhibitors of Eg5.
J.Med.Chem., 54:1576-, 2011

PubMed Abstract: The mitotic spindle is a validated target for cancer chemotherapy. Drugs such as taxanes and vinca alkaloids specifically target microtubules and cause the mitotic spindle to collapse. However, toxicity and resistance are problems associated with these drugs. Thus, alternative approaches to inhibiting the mitotic spindle are being pursued. These include targeting Eg5, a human kinesin involved in the formation of the bipolar spindle. We previously identified S-trityl-L-cysteine (STLC) as a potent allosteric inhibitor of Eg5. Here, we report the synthesis of a new series of STLC-like compounds with in vitro inhibition in the low nanomolar range. We also performed a multidrug resistance study in cell lines overexpressing P-glycoprotein and showed that some of these inhibitors may have the potential to overcome susceptibility to this efflux pump. Finally, we performed molecular docking of the compounds and determined the structures of two Eg5-inhibitor complexes to explain the structure-activity relationship of these compounds.

PubMed: 21344920
DOI: 10.1021/JM100991M

実験手法

X-RAY DIFFRACTION (2.6 Å)