@article {2303, title = {The crystal structure of MexR from Pseudomonas aeruginosa in complex with its antirepressor ArmR}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {105}, number = {39}, year = {2008}, note = {ISI Document Delivery No.: 386WWTimes Cited: 15Cited Reference Count: 41Wilke, Mark S. Heller, Markus Creagh, A. Louise Haynes, Charles A. McIntosh, Lawrence P. Poole, Keith Strynadka, Natalie C. J.}, month = {Sep}, pages = {14832-14837}, type = {Article}, abstract = {The intrinsic antimicrobial resistance of the opportunistic human pathogen Pseudomonas aeruginosa is compounded in mutant strains that overexpress multidrug efflux pumps such as the prominent drug-proton antiporter, MexAB-OprM. The primary regulator of the mexAB-oprM operon is the MarR family repressor, MexR. An additional repressor, NalC, also regulates mexAB-oprM by controlling expression of ArmR, an antirepressor peptide that is hypothesized to prevent the binding of MexR to its cognate DNA operator via an allosteric protein-peptide interaction. To better understand how ArmR modulates MexR, we determined the MexR-binding region of ArmR as its C-terminal 25 residues and solved the crystal structure of MexR in a 2: 1 complex with this ArmR fragment at 1.8 angstrom resolution. This structure reveals that the C-terminal residues of ArmR form a kinked alpha-helix, which occupies a pseudo-symmetrical and largely hydrophobic binding cavity located at the centre of the MexR dimer. Although the ArmR-binding cavity partially overlaps with the small molecule effector-binding sites of other MarR family members, it possesses a larger and more complex binding surface to accommodate the greater size and specific physicochemical properties of a peptide effector. Comparison with the structure of apo-MexR reveals that ArmR stabilizes a dramatic conformational change that is incompatible with DNA-binding. Thus, this work defines the structural mechanism by which ArmR allosterically derepresses MexR-controlled gene expression in P. aeruginosa and reveals important insights into the regulation of multidrug resistance.}, keywords = {DEINOCOCCUS-RADIODURANS, DNA-BINDING, EXPRESSION, GENE, gene regulation, MarR, MARR FAMILY, MECHANISM, mexAB-oprM, MULTIDRUG EFFLUX OPERON, OPRM, PA3719, protein peptide, REPRESSOR, TRANSCRIPTIONAL REGULATOR HUCR}, isbn = {0027-8424}, url = {://000261914300004}, author = {Wilke, M. S. and Heller, M. and Creagh, A. L. and Haynes, C. A. and McIntosh, L. P. and Poole, K. and Strynadka, N. C. J.} }