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

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 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2012-07-252012-09
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1261/rna.034819.112
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Titel: RNA
Genre der Quelle: Zeitschrift
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Seiten: - Band / Heft: 18 (9) Artikelnummer: - Start- / Endseite: 1605 - 1611 Identifikator: -