The activity of CouR, a MarR family transcriptional regulator, is modulated through a novel molecular mechanism

Otani, Hiroshi; Stogios, Peter J.; Xu, Xiaohui; Nocek, Boguslaw; Li, Shu -Nan; Savchenko, Alexei; Eltis, Lindsay D.

doi:10.1093/nar/gkv955

Title: The activity of CouR, a MarR family transcriptional regulator, is modulated through a novel molecular mechanism

Journal Article · Tue Sep 22 00:00:00 EDT 2015 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkv955· OSTI ID:1223714

Otani, Hiroshi ^[1]; Stogios, Peter J. ^[2]; Xu, Xiaohui ^[2]; Nocek, Boguslaw ^[3]; Li, Shu -Nan ^[1]; Savchenko, Alexei ^[2]; Eltis, Lindsay D. ^[1]

The Univ. of British Columbia, Vancouver, BC (Canada)
Univ. of Toronto, Toronto, ON (Canada)
Argonne National Lab. (ANL) and the Midwest Center for Structural Genomics, Lemont, IL (United States)

CouR, a MarR-type transcriptional repressor, regulates the cou genes, encoding p-hydroxycinnamate catabolism in the soil bacterium Rhodococcus jostii RHA1. The CouR dimer bound two molecules of the catabolite p-coumaroyl–CoA (K_d = 11 ± 1 μM). The presence of p-coumaroyl–CoA, but neither p-coumarate nor CoASH, abrogated CouR's binding to its operator DNA in vitro. The crystal structures of ligand-free CouR and its p-coumaroyl–CoA-bound form showed no significant conformational differences, in contrast to other MarR regulators. The CouR–p-coumaroyl–CoA structure revealed two ligand molecules bound to the CouR dimer with their phenolic moieties occupying equivalent hydrophobic pockets in each protomer and their CoA moieties adopting non-equivalent positions to mask the regulator's predicted DNA-binding surface. More specifically, the CoA phosphates formed salt bridges with predicted DNA-binding residues Arg36 and Arg38, changing the overall charge of the DNA-binding surface. The substitution of either arginine with alanine completely abrogated the ability of CouR to bind DNA. By contrast, the R36A/R38A double variant retained a relatively high affinity for p-coumaroyl–CoA (K_d = 89 ± 6 μM). Altogether, our data point to a novel mechanism of action in which the ligand abrogates the repressor's ability to bind DNA by steric occlusion of key DNA-binding residues and charge repulsion of the DNA backbone.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1223714

Alternate ID(s):: OSTI ID: 1258748

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 27 works

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