5TBW

Crystal structure of chlorolissoclimide bound to the yeast 80S ribosome

これはPDB形式変換不可エントリーです。

5TBW の概要

• エントリーDOI: 10.2210/pdb5tbw/pdb
• 分子名称: 25S ribosomal RNA, 60S ribosomal protein L8-A, 60S ribosomal protein L9-A, ... (87 entities in total)
• 機能のキーワード: protein translation inhibitor, complex, ribosome
• 由来する生物種: Saccharomyces cerevisiae (strain ATCC 204508 / S288c); 詳細
• タンパク質・核酸の鎖数: 159
• 化学式量合計: 6294772.15

構造登録者

Konst, Z.A.,Szklarski, A.R.,Pellegrino, S.,Michalak, S.E.,Meyer, M.,Zanette, C.,Cencic, R.,Nam, S.,Horne, D.A.,Pelletier, J.,Mobley, D.L.,Yusupova, G.,Yusupov, M.,Vanderwal, C.D. (登録日: 2016-09-13, 公開日: 2017-07-26, 最終更新日: 2024-01-17)

主引用文献

Konst, Z.A.,Szklarski, A.R.,Pellegrino, S.,Michalak, S.E.,Meyer, M.,Zanette, C.,Cencic, R.,Nam, S.,Voora, V.K.,Horne, D.A.,Pelletier, J.,Mobley, D.L.,Yusupova, G.,Yusupov, M.,Vanderwal, C.D.
Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides.
Nat Chem, 9:1140-1149, 2017

PubMed Abstract: The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semisynthesis and analogue-oriented synthesis approaches provide a series of lissoclimide natural products and analogues that expand the structure-activity relationships (SARs) in this family. The semisynthesis approach yielded significant quantities of chlorolissoclimide (CL) to permit an evaluation against the National Cancer Institute's 60-cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome. Although it shares a binding site with other imide-based natural product translation inhibitors, CL engages in a particularly interesting and novel face-on halogen-π interaction between the ligand's alkyl chloride and a guanine residue. Our analogue-oriented synthesis provides many more lissoclimide compounds, which were tested against aggressive human cancer cell lines and for protein synthesis inhibitory activity. Finally, computational modelling was used to explain the SARs of certain key compounds and set the stage for the structure-guided design of better translation inhibitors.

PubMed: 29064494
DOI: 10.1038/nchem.2800

実験手法

X-RAY DIFFRACTION (3 Å)