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  • The EMBO Journal (2005) 24, 674 - 682
  • doi:10.1038/sj.emboj.7600499

Published online: 3 February 2005

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

Elizabeth A Campbell1, Olga Pavlova2,3, Nikolay Zenkin2, Fred Leon1, Herbert Irschik4, Rolf Jansen4, Konstantin Severinov2 and Seth A Darst1

  1. The Rockefeller University, New York, NY, USA
  2. Department of Molecular Biology and Biochemistry, Waksman Institute, Rutgers University, Piscataway, NJ, USA
  3. Department of Virology, Faculty of Biology, Moscow State University, Moscow, Russia
  4. Department of Natural Products, Gesellschaft für Biotechnologische Forschung, Braunschweig, Germany

Correspondence to:

Seth A Darst, Laboratory of Molecular Biophysics, The Rockefeller University, Box 224, 1230 York Avenue, New York, NY 10021, USA. Tel.: +1 212 327 7479; Fax: +1 212 327 7477; E-mail: darst@rockefeller.edu or darst@rockvax.rockefeller.edu

Received 13 October 2004; Accepted 8 November 2004

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 beta 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.

  • Keywords:

    • rifampicin,
    • RNA polymerase,
    • sorangicin,
    • transcription
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