Structural highlights
Function
MTRR_NEIGO Controls the permeability of the cell envelope to hydrophobic compounds such as antibiotics and detergents (PubMed:8196548). Represses transcription of the mtrCDE-encoded efflux pump by binding within the mtrCDE promoter (PubMed:9209024, PubMed:23221802). Also negatively regulates the expression of farR, by binding to its promoter region, leading indirectly to the positive regulation of expression of the farAB-encoded efflux pump (PubMed:14645274).[1] [2] [3] [4]
Publication Abstract from PubMed
Mutations within the mtrR gene are commonly found amongst multidrug resistant clinical isolates of Neisseria gonorrhoeae, which has been labelled a superbug by the Centers for Disease Control and Prevention. These mutations appear to contribute to antibiotic resistance by interfering with the ability of MtrR to bind to and repress expression of its target genes, which include the mtrCDE multidrug efflux transporter genes and the rpoH oxidative stress response sigma factor gene. However, the DNA-recognition mechanism of MtrR and the consensus sequence within these operators to which MtrR binds has remained unknown. In this work, we report the crystal structures of MtrR bound to the mtrCDE and rpoH operators, which reveal a conserved, but degenerate, DNA consensus binding site 5'-MCRTRCRN4YGYAYGK-3'. We complement our structural data with a comprehensive mutational analysis of key MtrR-DNA contacts to reveal their importance for MtrR-DNA binding both in vitro and in vivo. Furthermore, we model and generate common clinical mutations of MtrR to provide plausible biochemical explanations for the contribution of these mutations to multidrug resistance in N. gonorrhoeae. Collectively, our findings unveil key biological mechanisms underlying the global stress responses of N. gonorrhoeae.
Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations.,Beggs GA, Ayala JC, Kavanaugh LG, Read TD, Hooks GM, Schumacher MA, Shafer WM, Brennan RG Nucleic Acids Res. 2021 Apr 19;49(7):4155-4170. doi: 10.1093/nar/gkab213. PMID:33784401[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lee EH, Rouquette-Loughlin C, Folster JP, Shafer WM. FarR regulates the farAB-encoded efflux pump of Neisseria gonorrhoeae via an MtrR regulatory mechanism. J Bacteriol. 2003 Dec;185(24):7145-52. doi: 10.1128/jb.185.24.7145-7152.2003. PMID:14645274 doi:http://dx.doi.org/10.1128/jb.185.24.7145-7152.2003
- ↑ Zalucki YM, Dhulipala V, Shafer WM. Dueling regulatory properties of a transcriptional activator (MtrA) and repressor (MtrR) that control efflux pump gene expression in Neisseria gonorrhoeae. MBio. 2012 Dec 4;3(6):e00446-12. doi: 10.1128/mBio.00446-12. PMID:23221802 doi:http://dx.doi.org/10.1128/mBio.00446-12
- ↑ Pan W, Spratt BG. Regulation of the permeability of the gonococcal cell envelope by the mtr system. Mol Microbiol. 1994 Feb;11(4):769-75. doi: 10.1111/j.1365-2958.1994.tb00354.x. PMID:8196548 doi:http://dx.doi.org/10.1111/j.1365-2958.1994.tb00354.x
- ↑ Lucas CE, Balthazar JT, Hagman KE, Shafer WM. The MtrR repressor binds the DNA sequence between the mtrR and mtrC genes of Neisseria gonorrhoeae. J Bacteriol. 1997 Jul;179(13):4123-8. doi: 10.1128/jb.179.13.4123-4128.1997. PMID:9209024 doi:http://dx.doi.org/10.1128/jb.179.13.4123-4128.1997
- ↑ Beggs GA, Ayala JC, Kavanaugh LG, Read TD, Hooks GM, Schumacher MA, Shafer WM, Brennan RG. Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations. Nucleic Acids Res. 2021 Apr 19;49(7):4155-4170. PMID:33784401 doi:10.1093/nar/gkab213
