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Structures of RNA polymerase-antibiotic complexes.

ABSTRACT: Inhibition of bacterial RNA polymerase (RNAP) is an established strategy for antituberculosis therapy and broad-spectrum antibacterial therapy. Crystal structures of RNAP-inhibitor complexes are available for four classes of antibiotics: rifamycins, sorangicin, streptolydigin, and myxopyronin. The structures define three different targets, and three different mechanisms, for inhibition of bacterial RNAP: (1) rifamycins and sorangicin bind near the RNAP active center and block extension of RNA products; (2) streptolydigin interacts with a target that overlaps the RNAP active center and inhibits conformational cycling of the RNAP active center; and (3) myxopyronin interacts with a target remote from the RNAP active center and functions by interfering with opening of the RNAP active-center cleft to permit entry and unwinding of DNA and/or by interfering with interactions between RNAP and the DNA template strand. The structures enable construction of homology models of pathogen RNAP-antibiotic complexes, enable in silico screening for new antibacterial agents, and enable rational design of improved antibacterial agents.

SUBMITTER: Ho MX

PROVIDER: S-EPMC2950656 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Structures of RNA polymerase-antibiotic complexes.

Ho Mary X MX Hudson Brian P BP Das Kalyan K Arnold Eddy E Ebright Richard H RH

Current opinion in structural biology 20091118 6

Inhibition of bacterial RNA polymerase (RNAP) is an established strategy for antituberculosis therapy and broad-spectrum antibacterial therapy. Crystal structures of RNAP-inhibitor complexes are available for four classes of antibiotics: rifamycins, sorangicin, streptolydigin, and myxopyronin. The structures define three different targets, and three different mechanisms, for inhibition of bacterial RNAP: (1) rifamycins and sorangicin bind near the RNAP active center and block extension of RNA pr ...[more]

PMID: 19926275

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Project description:RNA-dependent RNA polymerases play a vital role in the growth of RNA viruses where they are responsible for genome replication, but do so with rather low fidelity that allows for the rapid adaptation to different host cell environments. These polymerases are also a target for antiviral drug development. However, both drug discovery efforts and our understanding of fidelity determinants have been hampered by a lack of detailed structural information about functional polymerase-RNA complexes and the structural changes that take place during the elongation cycle. Many of the molecular details associated with nucleotide selection and catalysis were revealed in our recent structure of the poliovirus polymerase-RNA complex solved by first purifying and then crystallizing stalled elongation complexes. In the work presented here we extend that basic methodology to determine nine new structures of poliovirus, coxsackievirus, and rhinovirus elongation complexes at 2.2-2.9 Å resolution. The structures highlight conserved features of picornaviral polymerases and the interactions they make with the template and product RNA strands, including a tight grip on eight basepairs of the nascent duplex, a fully pre-positioned templating nucleotide, and a conserved binding pocket for the +2 position template strand base. At the active site we see a pre-bound magnesium ion and there is conservation of a non-standard backbone conformation of the template strand in an interaction that may aid in triggering RNA translocation via contact with the conserved polymerase motif B. Moreover, by engineering plasticity into RNA-RNA contacts, we obtain crystal forms that are capable of multiple rounds of in-crystal catalysis and RNA translocation. Together, the data demonstrate that engineering flexible RNA contacts to promote crystal lattice formation is a versatile platform that can be used to solve the structures of viral RdRP elongation complexes and their catalytic cycle intermediates.

Dataset Information

Structures of RNA polymerase-antibiotic complexes.

Publications

Structures of RNA polymerase-antibiotic complexes.

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