Download MendeleyMutation-Induced Population Shift in the Mexr Conformational Ensemble Disengages DNA Binding: A Novel Mechanism for Marr Family Derepression.
Anandapadamanaban, M., Pilstal, R., Andresen, C., Trewhella, J., Moche, M., Wallner, B., Sunnerhagen, M.(2016) Structure 24: 1311
- PubMed: 27427478
- DOI: https://doi.org/10.1016/j.str.2016.06.008
- Primary Citation of Related Structures:
4ZZL - PubMed 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.
Organizational Affiliation:
Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden.
