X-ray crystal structures of the Escherichia coli RNA polymerase in complex with benzoxazinorifamycins

Vadim Molodtsov, Irosha N. Nawarathne, Nathan T. Scharf, Paul D. Kirchhoff, H. D.Hollis Showalter, George A. Garcia, Katsuhiko Murakami

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Rifampin, a semisynthetic rifamycin, is the cornerstone of current tuberculosis treatment. Among many semisynthetic rifamycins, benzoxazinorifamycins have great potential for TB treatment due to their superior affinity for wild-type and rifampin-resistant Mycobacterium tuberculosis RNA polymerases and their reduced hepatic Cyp450 induction activity. In this study, we have determined the crystal structures of the Escherichia coli RNA polymerase complexes with two benzoxazinorifamycins. The ansa-naphthalene moieties of the benzoxazinorifamycins bind in a deep pocket of the β subunit, blocking the path of the RNA transcript. The C3′-tail of benzoxazinorifamycin fits a cavity between the β subunit and σ factor. We propose that in addition to blocking RNA exit, the benzoxazinorifamycin C3′-tail changes the σ region 3.2 loop position, which influences the template DNA at the active site, thereby reducing the efficiency of transcription initiation. This study supports expansion of structure-activity relationships of benzoxazinorifamycins inhibition of RNA polymerase toward uncovering superior analogues with development potential.

Original languageEnglish (US)
Pages (from-to)4758-4763
Number of pages6
JournalJournal of Medicinal Chemistry
Volume56
Issue number11
DOIs
StatePublished - Jun 13 2013

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KRM 1648
DNA-Directed RNA Polymerases
X-Rays
Escherichia coli
Rifampin
Rifamycins
RNA
Structure-Activity Relationship
Mycobacterium tuberculosis
Catalytic Domain
Tuberculosis

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Molodtsov, V., Nawarathne, I. N., Scharf, N. T., Kirchhoff, P. D., Showalter, H. D. H., Garcia, G. A., & Murakami, K. (2013). X-ray crystal structures of the Escherichia coli RNA polymerase in complex with benzoxazinorifamycins. Journal of Medicinal Chemistry, 56(11), 4758-4763. https://doi.org/10.1021/jm4004889
Molodtsov, Vadim ; Nawarathne, Irosha N. ; Scharf, Nathan T. ; Kirchhoff, Paul D. ; Showalter, H. D.Hollis ; Garcia, George A. ; Murakami, Katsuhiko. / X-ray crystal structures of the Escherichia coli RNA polymerase in complex with benzoxazinorifamycins. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 11. pp. 4758-4763.
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Molodtsov, V, Nawarathne, IN, Scharf, NT, Kirchhoff, PD, Showalter, HDH, Garcia, GA & Murakami, K 2013, 'X-ray crystal structures of the Escherichia coli RNA polymerase in complex with benzoxazinorifamycins', Journal of Medicinal Chemistry, vol. 56, no. 11, pp. 4758-4763. https://doi.org/10.1021/jm4004889

X-ray crystal structures of the Escherichia coli RNA polymerase in complex with benzoxazinorifamycins. / Molodtsov, Vadim; Nawarathne, Irosha N.; Scharf, Nathan T.; Kirchhoff, Paul D.; Showalter, H. D.Hollis; Garcia, George A.; Murakami, Katsuhiko.

In: Journal of Medicinal Chemistry, Vol. 56, No. 11, 13.06.2013, p. 4758-4763.

Research output: Contribution to journalArticle

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T1 - X-ray crystal structures of the Escherichia coli RNA polymerase in complex with benzoxazinorifamycins

AU - Molodtsov, Vadim

AU - Nawarathne, Irosha N.

AU - Scharf, Nathan T.

AU - Kirchhoff, Paul D.

AU - Showalter, H. D.Hollis

AU - Garcia, George A.

AU - Murakami, Katsuhiko

PY - 2013/6/13

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N2 - Rifampin, a semisynthetic rifamycin, is the cornerstone of current tuberculosis treatment. Among many semisynthetic rifamycins, benzoxazinorifamycins have great potential for TB treatment due to their superior affinity for wild-type and rifampin-resistant Mycobacterium tuberculosis RNA polymerases and their reduced hepatic Cyp450 induction activity. In this study, we have determined the crystal structures of the Escherichia coli RNA polymerase complexes with two benzoxazinorifamycins. The ansa-naphthalene moieties of the benzoxazinorifamycins bind in a deep pocket of the β subunit, blocking the path of the RNA transcript. The C3′-tail of benzoxazinorifamycin fits a cavity between the β subunit and σ factor. We propose that in addition to blocking RNA exit, the benzoxazinorifamycin C3′-tail changes the σ region 3.2 loop position, which influences the template DNA at the active site, thereby reducing the efficiency of transcription initiation. This study supports expansion of structure-activity relationships of benzoxazinorifamycins inhibition of RNA polymerase toward uncovering superior analogues with development potential.

AB - Rifampin, a semisynthetic rifamycin, is the cornerstone of current tuberculosis treatment. Among many semisynthetic rifamycins, benzoxazinorifamycins have great potential for TB treatment due to their superior affinity for wild-type and rifampin-resistant Mycobacterium tuberculosis RNA polymerases and their reduced hepatic Cyp450 induction activity. In this study, we have determined the crystal structures of the Escherichia coli RNA polymerase complexes with two benzoxazinorifamycins. The ansa-naphthalene moieties of the benzoxazinorifamycins bind in a deep pocket of the β subunit, blocking the path of the RNA transcript. The C3′-tail of benzoxazinorifamycin fits a cavity between the β subunit and σ factor. We propose that in addition to blocking RNA exit, the benzoxazinorifamycin C3′-tail changes the σ region 3.2 loop position, which influences the template DNA at the active site, thereby reducing the efficiency of transcription initiation. This study supports expansion of structure-activity relationships of benzoxazinorifamycins inhibition of RNA polymerase toward uncovering superior analogues with development potential.

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Molodtsov V, Nawarathne IN, Scharf NT, Kirchhoff PD, Showalter HDH, Garcia GA et al. X-ray crystal structures of the Escherichia coli RNA polymerase in complex with benzoxazinorifamycins. Journal of Medicinal Chemistry. 2013 Jun 13;56(11):4758-4763. https://doi.org/10.1021/jm4004889