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Structure. 2016 Aug 2;24(8):1311-1321. doi: 10.1016/j.str.2016.06.008. Epub 2016 Jul 14.

Mutation-Induced Population Shift in the MexR Conformational Ensemble Disengages DNA Binding: A Novel Mechanism for MarR Family Derepression.

Author information

1
Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden.
2
Division of Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden.
3
Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden; School of Molecular Bioscience, The University of Sydney, Sydney, NSW 2006, Australia.
4
Department of Medical Biochemistry and Biophysics, Protein Science Facility, Karolinska Institutet, 171 77 Stockholm, Sweden.
5
Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden. Electronic address: maria.sunnerhagen@liu.se.

Abstract

MexR is a repressor of the MexAB-OprM multidrug efflux pump operon of Pseudomonas aeruginosa, where DNA-binding impairing mutations lead to multidrug resistance (MDR). Surprisingly, the crystal structure of an MDR-conferring MexR mutant R21W (2.19 Å) presented here is closely similar to wild-type MexR. However, our extended analysis, by molecular dynamics and small-angle X-ray scattering, reveals that the mutation stabilizes a ground state that is deficient of DNA binding and is shared by both mutant and wild-type MexR, whereas the DNA-binding state is only transiently reached by the more flexible wild-type MexR. This population shift in the conformational ensemble is effected by mutation-induced allosteric coupling of contact networks that are independent in the wild-type protein. We propose that the MexR-R21W mutant mimics derepression by small-molecule binding to MarR proteins, and that the described allosteric model based on population shifts may also apply to other MarR family members.

PMID:
27427478
DOI:
10.1016/j.str.2016.06.008
[Indexed for MEDLINE]
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