5OV7

tubulin - rigosertib complex

5OV7 の概要

• エントリーDOI: 10.2210/pdb5ov7/pdb
• 分子名称: Tubulin alpha-1B chain, N-[2-methoxy-5-({[(E)-2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonyl}methyl)phenyl]glycine, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (13 entities in total)
• 機能のキーワード: cell cycle, tubulin fold, cytoskeleton, microtubule
• 由来する生物種: Rattus norvegicus (Norway Rat); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 265881.68

構造登録者

Menchon, G.,Prota, A.E.,Steinmetz, M.,Jost, M. (登録日: 2017-08-28, 公開日: 2017-10-11, 最終更新日: 2024-01-17)

主引用文献

Jost, M.,Chen, Y.,Gilbert, L.A.,Horlbeck, M.A.,Krenning, L.,Menchon, G.,Rai, A.,Cho, M.Y.,Stern, J.J.,Prota, A.E.,Kampmann, M.,Akhmanova, A.,Steinmetz, M.O.,Tanenbaum, M.E.,Weissman, J.S.
Combined CRISPRi/a-Based Chemical Genetic Screens Reveal that Rigosertib Is a Microtubule-Destabilizing Agent.
Mol. Cell, 68:210-223.e6, 2017

PubMed Abstract: Chemical libraries paired with phenotypic screens can now readily identify compounds with therapeutic potential. A central limitation to exploiting these compounds, however, has been in identifying their relevant cellular targets. Here, we present a two-tiered CRISPR-mediated chemical-genetic strategy for target identification: combined genome-wide knockdown and overexpression screening as well as focused, comparative chemical-genetic profiling. Application of these strategies to rigosertib, a drug in phase 3 clinical trials for high-risk myelodysplastic syndrome whose molecular target had remained controversial, pointed singularly to microtubules as rigosertib's target. We showed that rigosertib indeed directly binds to and destabilizes microtubules using cell biological, in vitro, and structural approaches. Finally, expression of tubulin with a structure-guided mutation in the rigosertib-binding pocket conferred resistance to rigosertib, establishing that rigosertib kills cancer cells by destabilizing microtubules. These results demonstrate the power of our chemical-genetic screening strategies for pinpointing the physiologically relevant targets of chemical agents.

PubMed: 28985505
DOI: 10.1016/j.molcel.2017.09.012

実験手法

X-RAY DIFFRACTION (2.402 Å)