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Mutation-induced population shift in the MexR conformational ensemble disengages DNAbinding: a novel mechanism for MarR family derepression

DOI: 10.1016/j.str.2016.06.008 DOI Help

Authors: Madhanagopal Anandapadamanaban (Linköping University) , Robert Pilstål (Linköping University) , Cecilia Andresen (Linköping University) , Jill Trewhella (Linköping University; The University of Sydney) , Martin Moche (Karolinska Institutet) , Björn Wallner (Linköping University) , Maria Sunnerhagen (Linköping University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure , VOL 24 , PAGES 1311 - 1321

State: Published (Approved)
Published: August 2016
Diamond Proposal Number(s): 6603

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 A) 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.

Diamond Keywords: Bacteria

Subject Areas: Medicine, Biology and Bio-materials

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 09/09/2016 19:50

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)