Structural, functional, and genetic analysis of sorangicin inhibition of bacterial RNA polymerase

Elizabeth A. Campbell, Olga Pavlova, Nikolay Zenkin, Fred Leon, Herbert Irschik, Rolf Jansen, Konstantin Severinov, Seth A. Darst

Research output: Contribution to journalArticlepeer-review

111 Citations (Scopus)

Abstract

A combined structural, functional, and genetic approach was used to investigate inhibition of bacterial RNA polymerase (RNAP) by sorangicin (Sor), a macrolide polyether antibiotic. Sor lacks chemical and structural similarity to the ansamycin rifampicin (Rif), an RNAP inhibitor widely used to treat tuberculosis. Nevertheless, structural analysis revealed Sor binds in the same RNAP β subunit pocket as Rif, with almost complete overlap of RNAP binding determinants, and functional analysis revealed that both antibiotics inhibit transcription by directly blocking the path of the elongating transcript at a length of 2-3 nucleotides. Genetic analysis indicates that Rif binding is extremely sensitive to mutations expected to change the shape of the antibiotic binding pocket, while Sor is not. We suggest that conformational flexibility of Sor, in contrast to the rigid conformation of Rif, allows Sor to adapt to changes in the binding pocket. This has important implications for drug design against rapidly mutating targets.

Original languageEnglish
Pages (from-to)674-682
Number of pages9
JournalEMBO Journal
Volume24
Issue number4
DOIs
Publication statusPublished - 23 Feb 2005
Externally publishedYes

Keywords

  • Rifampicin
  • RNA polymerase
  • Sorangicin
  • Transcription

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