Dynamic multidrug recognition by multidrug transcriptional repressor LmrR.
LmrR is a multidrug transcriptional repressor that controls the expression of a major multidrug transporter, LmrCD, in Lactococcus lactis. However, the molecular mechanism by which LmrR binds to structurally unrelated compounds and is released from the promoter region remains largely unknown. Here, we structurally and dynamically characterized LmrR in the apo, compound-bound and promoter-bound states. The compound-binding site of LmrR exhibits ps-μs dynamics in the apo state, and compound ligation shifts the preexisting conformational equilibrium to varying extents to achieve multidrug recognition. Meanwhile, the compound binding induces redistribution of ps-ns dynamics to the allosteric sites, which entropically favors the high-affinity recognition. Furthermore, the reciprocal compound/promoter binding by LmrR is achieved by the incompatible conformational ensembles between the compound- and promoter-bound states. Collectively, the data show how LmrR can dynamically exert its functions through promiscuous multi-target interactions, in a manner that cannot be understood by a static structural view.
1] 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 [2] JST, PRESTO, Aomi 2-3-26, Koto-ku, Tokyo 135-0064, Japan.
Koh
K
Takeuchi
1] 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 [2] Research and Development Department, Japan Biological Informatics Consortium, Tokyo, Japan. Aomi 2-3-26, Koto-ku, Tokyo 135-0064, Japan [3] Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Yuji
Y
Tokunaga
Research and Development Department, Japan Biological Informatics Consortium, Tokyo, Japan. Aomi 2-3-26, Koto-ku, Tokyo 135-0064, Japan.
Misaki
M
Imai
1] 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 [2] Graduate School of Medical Life Science, Yokohama City University, Kanagawa 230-0045, Japan.
Hideo
H
Takahashi
1] 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 [2] Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Ichio
I
Shimada
D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003630:Daunorubicin / Q000737:chemistry / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D004996:Ethidium / Q000737:chemistry / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial; D013294:Lactococcus lactis / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012235:Rhodamines / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic
D001562:Benzimidazoles; D003630:Daunorubicin; D004996:Ethidium; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012097:Repressor Proteins; D012235:Rhodamines; C513418:LmrC protein, Lactococcus lactis; C513419:LmrD protein, Lactococcus lactis; C026188:rhodamine 6G; C017807:bisbenzimide ethoxide trihydrochloride