4ZZL

MexR R21W derepressor mutant causing multidrug resistance in P. aeruginosa by mexAB-oprM efflux pump expression

Summary for 4ZZL

• Entry DOI: 10.2210/pdb4zzl/pdb
• Descriptor: MULTIDRUG RESISTANCE OPERON REPRESSOR, GLYCEROL (3 entities in total)
• Functional Keywords: transcription, mexr, mexab-oprm efflux pump, md simulation
• Biological source: PSEUDOMONAS AERUGINOSA
• Total number of polymer chains: 2
• Total formula weight: 36910.20

Authors

Anandapadamanaban, M.,Pilstal, R.,Ziauddin, J.M.E.,Moche, M.,Wallner, B.,Sunnerhagen, M. (deposition date: 2015-04-10, release date: 2016-07-27, Last modification date: 2024-01-10)

Primary citation

Anandapadamanaban, M.,Pilstal, R.,Andresen, C.,Trewhella, J.,Moche, M.,Wallner, B.,Sunnerhagen, M.
Mutation-Induced Population Shift in the Mexr Conformational Ensemble Disengages DNA Binding: A Novel Mechanism for Marr Family Derepression.
Structure, 24:1311-, 2016

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.

PubMed: 27427478
DOI: 10.1016/J.STR.2016.06.008

Experimental method

X-RAY DIFFRACTION (2.19 Å)