Dynamic equilibrium on DNA defines transcriptional regulation of a multidrug binding transcriptional repressor, LmrR.
LmrR is a multidrug binding transcriptional repressor that controls the expression of a major multidrug transporter, LmrCD, in Lactococcus lactis. Promiscuous compound ligations reduce the affinity of LmrR for the lmrCD operator by several fold to release the transcriptional repression; however, the affinity reduction is orders of magnitude smaller than that of typical transcriptional repressors. Here, we found that the transcriptional regulation of LmrR is achieved through an equilibrium between the operator-bound and non-specific DNA-adsorption states in vivo. The effective dissociation constant of LmrR for the lmrCD operator under the equilibrium is close to the endogenous concentration of LmrR, which allows a substantial reduction of LmrR occupancy upon compound ligations. Therefore, LmrR represents a dynamic type of transcriptional regulation of prokaryotic multidrug resistance systems, where the small affinity reduction induced by compounds is coupled to the functional relocalization of the repressor on the genomic DNA via nonspecific DNA adsorption.
Biomedicinal Information Research Center & Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Aomi 2-3-26, Koto-ku, Tokyo, 135-0064, Japan.|PRESTO, JST, Aomi 2-3-26, Koto-ku, Tokyo, 135-0064, Japan.
Koh
K
Takeuchi
Research and Development Department, Japan Biological Informatics Consortium, Aomi 2-3-26, Koto-ku, Tokyo, 135-0064, Japan.
Misaki
M
Imai
Biomedicinal Information Research Center & Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Aomi 2-3-26, Koto-ku, Tokyo, 135-0064, Japan. shimada@iw-nmr.f.u-tokyo.ac.jp.|Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. shimada@iw-nmr.f.u-tokyo.ac.jp.
Ichio
I
Shimada
D000900:Anti-Bacterial Agents / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial; D015964:Gene Expression Regulation, Bacterial; D013294:Lactococcus lactis / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics; D009875:Operator Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012097:Repressor Proteins; C513418:LmrC protein, Lactococcus lactis; C513419:LmrD protein, Lactococcus lactis