Mutation-Induced Population Shift in the MexR Conformational Ensemble Disengages DNA Binding: A Novel Mechanism for MarR Family Derepression
2016 (English)In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 24, no 8, 1311-1321 p.Article in journal (Refereed) Published
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 angstrom) presented here is closely similar to wildtype 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.
Place, publisher, year, edition, pages
CELL PRESS , 2016. Vol. 24, no 8, 1311-1321 p.
IdentifiersURN: urn:nbn:se:liu:diva-131908DOI: 10.1016/j.str.2016.06.008ISI: 000383244600012PubMedID: 27427478OAI: oai:DiVA.org:liu-131908DiVA: diva2:1034861
Funding Agencies|European Communitys Seventh Framework Program (FP7) under BioStruct-X ; Swedish e-Science Research Center; Swedish Research Council; Tage Erlander Visiting Professor grant2016-10-132016-10-112016-10-13