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Science 24 October 2003:
Vol. 302. no. 5645, pp. 650 - 654
DOI: 10.1126/science.1087526
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Reports

A New Class of Bacterial RNA Polymerase Inhibitor Affects Nucleotide Addition

Irina Artsimovitch,1* Clement Chu,2 A. Simon Lynch,2{dagger} Robert Landick1{dagger}

RNA polymerase (RNAP) is the central enzyme of gene expression. Despite availability of crystal structures, details of its nucleotide addition cycle remain obscure. We describe bacterial RNAP inhibitors (the CBR703 series) whose properties illuminate this mechanism. These compounds inhibit known catalytic activities of RNAP (nucleotide addition, pyrophosphorolysis, and Gre-stimulated transcript cleavage) but not translocation of RNA or DNA when translocation is uncoupled from catalysis. CBR703-resistance substitutions occur on an outside surface of RNAP opposite its internal active site. We propose that CBR703 compounds inhibit nucleotide addition allosterically by hindering movements of active site structures that are linked to the CBR703 binding site through a bridge helix.

1 Department of Bacteriology, University of Wisconsin, Madison, WI 53706, USA.
2 Cumbre Inc., 1502 Viceroy Drive, Dallas, TX 75235, USA.

* Present address: Department of Microbiology, Ohio State University, Columbus, OH 43210, USA.

{dagger} To whom correspondence should be addressed. E-mail: simon.lynch{at}cumbre.net (A.S.L.); landick{at}bact.wisc.edu (R.L.)

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