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  Molecular architecture of Zinc chelating small molecules that inhibit spliceosome assembly at an early stage.

Patil, V., Canzoneri, J. C., Samatov, T. R., Lührmann, R., & Oyelere, A. K. (2012). Molecular architecture of Zinc chelating small molecules that inhibit spliceosome assembly at an early stage. RNA, 18(9), 1605-1611. doi:10.1261/rna.034819.112.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000F-A536-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-8238-D
Genre: Journal Article

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Patil, V., Author
Canzoneri, J. C., Author
Samatov, T. R.1, Author              
Lührmann, R.1, Author              
Oyelere, A. K., Author
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1Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              

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 Abstract: The removal of intervening sequences (introns) from a primary RNA transcript is catalyzed by the spliceosome, a large ribonucleoprotein complex. At the start of each splicing cycle, the spliceosome assembles anew in a sequentially ordered manner on the pre-mRNA intron to be removed. We describe here the identification of a series of naphthalen-2-yl hydroxamate compounds that inhibit pre-mRNA splicing in vitro with mid- to high-micromolar values of IC50. These hydroxamates stall spliceosome assembly at the A complex stage. A structure-activity analysis of lead compounds revealed three pharmacophores that are essential for splicing inhibition. Specifically, a hydroxamate as a zinc-binding group and a 6-methoxynaphthalene cap group are both critical, and a linker chain comprising eight to nine methylene groups is also important, for the specific binding to the docking site of a target protein molecule and precise positioning of the zinc binding group. As we found no correlation between the inhibition patterns of known histone deacetylases on the one hand and pre-mRNA splicing on the other, we conclude that these compounds may function through the inhibition of the activities of other, at present, unknown spliceosome-associated zinc metalloprotein(s).

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Language(s): eng - English
 Dates: 2012-07-252012-09
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1261/rna.034819.112
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Title: RNA
Source Genre: Journal
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Pages: - Volume / Issue: 18 (9) Sequence Number: - Start / End Page: 1605 - 1611 Identifier: -