Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin

被引：672

作者：

Schneider-Poetsch, Tilman ^{[1
]}

Ju, Jianhua ^{[2
]}

Eyler, Daniel E. ^{[3
]}

Dang, Yongjun ^{[1
]}

Bhat, Shridhar ^{[1
]}

Merrick, William C. ^{[4
]}

Green, Rachel ^{[3
]}

Shen, Ben ^{[2
,5
,6
]}

Liu, Jun O. ^{[1
,7
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[2] Univ Wisconsin, Div Pharmaceut Sci, Madison, WI USA

[3] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA

[4] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA

[5] Univ Wisconsin, Natl Cooperat Drug Discovery Grp, Madison, WI USA

[6] Univ Wisconsin, Dept Chem, Madison, WI 53706 USA

[7] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

来源：

NATURE CHEMICAL BIOLOGY | 2010年 / 6卷 / 03期

关键词：

STREPTOMYCES SP MK929-43F1; TRANSFORMED NIH/3T3 CELLS; CRICKET PARALYSIS VIRUS; 23S RIBOSOMAL-RNA; PROTEIN-SYNTHESIS; ISO-MIGRASTATIN; ANTIFUNGAL ANTIBIOTICS; BIOLOGICAL-ACTIVITY; ENTRY SITE; IN-VITRO;

D O I：

10.1038/NCHEMBIO.304

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Although the protein synthesis inhibitor cycloheximide (CHX) has been known for decades, its precise mechanism of action remains incompletely understood. The glutarimide portion of CHX is seen in a family of structurally related natural products including migrastatin, isomigrastatin and lactimidomycin (LTM). We found that LTM, isomigrastatin and analogs have a potent antiproliferative effect on tumor cell lines and selectively inhibit translation. A systematic comparative study of the effects of CHX and LTM on protein synthesis revealed both similarities and differences between the two inhibitors. Both LTM and CHX were found to block the translocation step in elongation. Footprinting experiments revealed protection of a single cytidine nucleotide (C3993) in the E-site of the 60S ribosomal subunit, thus defining a common binding pocket for the two inhibitors in the ribosome. These results shed new light on the molecular mechanism of inhibition of translation elongation by both CHX and LTM.

引用

页码：209 / 217

页数：9

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