Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin

Tilman Schneider-Poetsch; Jianhua Ju; Daniel E. Eyler; Yongjun Dang; Shridhar Bhat; William C. Merrick; Rachel Green; Ben Shen; Jun O. Liu

doi:10.1038/nchembio.304

Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin

Tilman Schneider-Poetsch, Jianhua Ju, Daniel E. Eyler, Yongjun Dang, Shridhar Bhat, William C. Merrick, Rachel Green, Ben Shen, Jun O. Liu

Research output: Contribution to journal › Article › peer-review

464 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	209-217
Number of pages	9
Journal	Nature chemical biology
Volume	6
Issue number	3
DOIs	https://doi.org/10.1038/nchembio.304
State	Published - Mar 2010

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1038/nchembio.304

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title = "Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin",

abstract = "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.",

author = "Tilman Schneider-Poetsch and Jianhua Ju and Eyler, {Daniel E.} and Yongjun Dang and Shridhar Bhat and Merrick, {William C.} and Rachel Green and Ben Shen and Liu, {Jun O.}",

note = "Funding Information: We are indebted to J. Boeke (Johns Hopkins University) and J. Warner (Albert Einstein College of Medicine) for the CHX-resistant strains of S. cerevisiae, J. Pelletier (McGill University) for providing us with the HCV and EMCV IRES reporter constructs and P. Sarnow (Stanford University) for providing the CrPV vector. We thank the laboratories of J. Hart, P. Englund, J. Lorsch, S. Sukumar and R. Rao for use of specialized equipment and constructive advice. This work was supported in part by grants from the US National Cancer Institute and the Flight Attendant Medical Research Institute (J.O.L.) and by US National Cancer Institute grants CA106150 and CA113297 (B.S.).",

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AU - Schneider-Poetsch, Tilman

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AU - Bhat, Shridhar

AU - Merrick, William C.

AU - Green, Rachel

AU - Shen, Ben

AU - Liu, Jun O.

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Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin

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