Structural mechanism for rifampicin inhibition of bacterial RNA polymerase

Elizabeth A. Campbell; Nataliya Korzheva; Arkady Mustaev; Katsuhiko Murakami; Satish Nair; Alex Goldfarb; Seth A. Darst

doi:10.1016/S0092-8674(01)00286-0

Structural mechanism for rifampicin inhibition of bacterial RNA polymerase

Elizabeth A. Campbell
, Nataliya Korzheva
, Arkady Mustaev
, Katsuhiko Murakami
, Satish Nair
, Alex Goldfarb
, Seth A. Darst

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

1320 Scopus citations

Abstract

Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP). We determined the crystal structure of Thermus aquaticus core RNAP complexed with Rif. The inhibitor binds in a pocket of the RNAP β subunit deep within the DNA/RNA channel, but more than 12 Å away from the active site. The structure, combined with biochemical results, explains the effects of Rif on RNAP function and indicates that the inhibitor acts by directly blocking the path of the elongating RNA when the transcript becomes 2 to 3 nt in length.

Original language	English (US)
Pages (from-to)	901-912
Number of pages	12
Journal	Cell
Volume	104
Issue number	6
DOIs	https://doi.org/10.1016/S0092-8674(01)00286-0
State	Published - Mar 23 2001

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

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10.1016/S0092-8674(01)00286-0

Cite this

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title = "Structural mechanism for rifampicin inhibition of bacterial RNA polymerase",

abstract = "Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP). We determined the crystal structure of Thermus aquaticus core RNAP complexed with Rif. The inhibitor binds in a pocket of the RNAP β subunit deep within the DNA/RNA channel, but more than 12 {\AA} away from the active site. The structure, combined with biochemical results, explains the effects of Rif on RNAP function and indicates that the inhibitor acts by directly blocking the path of the elongating RNA when the transcript becomes 2 to 3 nt in length.",

author = "Campbell, \{Elizabeth A.\} and Nataliya Korzheva and Arkady Mustaev and Katsuhiko Murakami and Satish Nair and Alex Goldfarb and Darst, \{Seth A.\}",

note = "Funding Information: We are indebted to A. Joachimiak, S. L. Ginell, and F. J. Rotella at the Advanced Photon Source Structural Biology Center for support during data collection. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Biological and Environmental Research, under Contract No. W-31-109-ENG-38. We thank V. Nikiforov and J. McKinney for invaluable discussions. E. C. was supported by a Kluge postdoctoral fellowship and a National Research Service Award (NIH GM20470). K. M. was supported by a Human Frontiers Sciences Program postdoctoral fellowship and a Norman and Rosita Winston postdoctoral fellowship. This work was supported by NIH grants GM49242 and GM30717 to A. G., and GM53759 and GM61898 to S. A. D. ",

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AU - Nair, Satish

AU - Goldfarb, Alex

AU - Darst, Seth A.

N1 - Funding Information: We are indebted to A. Joachimiak, S. L. Ginell, and F. J. Rotella at the Advanced Photon Source Structural Biology Center for support during data collection. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Biological and Environmental Research, under Contract No. W-31-109-ENG-38. We thank V. Nikiforov and J. McKinney for invaluable discussions. E. C. was supported by a Kluge postdoctoral fellowship and a National Research Service Award (NIH GM20470). K. M. was supported by a Human Frontiers Sciences Program postdoctoral fellowship and a Norman and Rosita Winston postdoctoral fellowship. This work was supported by NIH grants GM49242 and GM30717 to A. G., and GM53759 and GM61898 to S. A. D.

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Y1 - 2001/3/23

N2 - Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP). We determined the crystal structure of Thermus aquaticus core RNAP complexed with Rif. The inhibitor binds in a pocket of the RNAP β subunit deep within the DNA/RNA channel, but more than 12 Å away from the active site. The structure, combined with biochemical results, explains the effects of Rif on RNAP function and indicates that the inhibitor acts by directly blocking the path of the elongating RNA when the transcript becomes 2 to 3 nt in length.

AB - Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP). We determined the crystal structure of Thermus aquaticus core RNAP complexed with Rif. The inhibitor binds in a pocket of the RNAP β subunit deep within the DNA/RNA channel, but more than 12 Å away from the active site. The structure, combined with biochemical results, explains the effects of Rif on RNAP function and indicates that the inhibitor acts by directly blocking the path of the elongating RNA when the transcript becomes 2 to 3 nt in length.

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Structural mechanism for rifampicin inhibition of bacterial RNA polymerase

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