{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:58:43Z","timestamp":1789153123103,"version":"build-2803163510"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2014,11,18]],"date-time":"2014-11-18T00:00:00Z","timestamp":1416268800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2014,11,18]],"date-time":"2014-11-18T00:00:00Z","timestamp":1416268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    LmrR is a multidrug transcriptional repressor that controls the expression of a major multidrug transporter, LmrCD, in\n                    <jats:italic>Lactococcus lactis<\/jats:italic>\n                    . 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\n                    <jats:italic>apo<\/jats:italic>\n                    , compound-bound and promoter-bound states. The compound-binding site of LmrR exhibits ps\u2013\u03bcs dynamics in the\n                    <jats:italic>apo<\/jats:italic>\n                    state and compound ligation shifts the preexisting conformational equilibrium to varying extents to achieve multidrug recognition. Meanwhile, the compound binding induces redistribution of ps\u2013ns 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.\n                  <\/jats:p>","DOI":"10.1038\/srep06922","type":"journal-article","created":{"date-parts":[[2014,11,18]],"date-time":"2014-11-18T05:17:51Z","timestamp":1416287871000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Dynamic multidrug recognition by multidrug transcriptional repressor LmrR"],"prefix":"10.1038","volume":"4","author":[{"given":"Koh","family":"Takeuchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Tokunaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misaki","family":"Imai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichio","family":"Shimada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,11,18]]},"reference":[{"key":"BFsrep06922_CR1","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/0966-842X(94)90654-8","volume":"2","author":"D Ma","year":"1994","unstructured":"Ma, D., Cook, D. N., Hearst, J. E. & Nikaido, H. Efflux pumps and drug resistance in Gram-negative bacteria. Trends in Microbiology 2, 489\u2013493 (1994).","journal-title":"Trends in Microbiology"},{"key":"BFsrep06922_CR2","first-page":"265","volume":"12","author":"MH Saier Jr","year":"1998","unstructured":"Saier, M. H., Jr et al. Evolutionary origins of multidrug and drug-specific efflux pumps in bacteria. Faseb j 12, 265\u201374 (1998).","journal-title":"Faseb j"},{"key":"BFsrep06922_CR3","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/978-1-4615-4897-3_8","volume":"456","author":"HW van Veen","year":"1998","unstructured":"van Veen, H. W. & Konings, W. N. Structure and function of multidrug transporters. Adv Exp Med Biol 456, 145\u201358 (1998).","journal-title":"Adv Exp Med Biol"},{"key":"BFsrep06922_CR4","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1046\/j.1365-2958.2002.03039.x","volume":"45","author":"MA Schumacher","year":"2002","unstructured":"Schumacher, M. A. & Brennan, R. G. Structural mechanisms of multidrug recognition and regulation by bacterial multidrug transcription factors. Mol Microbiol 45, 885\u2013893 (2002).","journal-title":"Mol Microbiol"},{"key":"BFsrep06922_CR5","doi-asserted-by":"crossref","first-page":"14581","DOI":"10.1074\/jbc.M010173200","volume":"276","author":"A Geick","year":"2001","unstructured":"Geick, A., Eichelbaum, M. & Burk, O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276, 14581\u20137 (2001).","journal-title":"J Biol Chem"},{"key":"BFsrep06922_CR6","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/316817a0","volume":"316","author":"JR Riordan","year":"1985","unstructured":"Riordan, J. R. et al. Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. Nature 316, 817\u20139 (1985).","journal-title":"Nature"},{"key":"BFsrep06922_CR7","doi-asserted-by":"crossref","first-page":"6957","DOI":"10.1128\/jb.176.22.6957-6964.1994","volume":"176","author":"H Bolhuis","year":"1994","unstructured":"Bolhuis, H. et al. Proton motive force-driven and ATP-dependent drug extrusion systems in multidrug-resistant Lactococcus lactis. J Bacteriol 176, 6957\u201364 (1994).","journal-title":"J Bacteriol"},{"key":"BFsrep06922_CR8","doi-asserted-by":"crossref","first-page":"34449","DOI":"10.1074\/jbc.M404072200","volume":"279","author":"J Lubelski","year":"2004","unstructured":"Lubelski, J., Mazurkiewicz, P., van Merkerk, R., Konings, W. N. & Driessen, A. J. ydaG and ydbA of Lactococcus lactis encode a heterodimeric ATP-binding cassette-type multidrug transporter. J Biol Chem 279, 34449\u201355 (2004).","journal-title":"J Biol Chem"},{"key":"BFsrep06922_CR9","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1111\/j.1365-2958.2006.05267.x","volume":"61","author":"J Lubelski","year":"2006","unstructured":"Lubelski, J. et al. LmrCD is a major multidrug resistance transporter in Lactococcus lactis. Mol Microbiol 61, 771\u201381 (2006).","journal-title":"Mol Microbiol"},{"key":"BFsrep06922_CR10","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1128\/JB.01151-07","volume":"190","author":"H Agustiandari","year":"2008","unstructured":"Agustiandari, H., Lubelski, J., van den Berg van Saparoea, H. B., Kuipers, O. P. & Driessen, A. J. LmrR is a transcriptional repressor of expression of the multidrug ABC transporter LmrCD in Lactococcus lactis. J Bacteriol 190, 759\u201363 (2008).","journal-title":"J Bacteriol"},{"key":"BFsrep06922_CR11","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.sbi.2010.06.003","volume":"20","author":"H Wade","year":"2010","unstructured":"Wade, H. MD recognition by MDR gene regulators. Curr Opin Struct Biol 20, 489\u2013496 (2010).","journal-title":"Curr Opin Struct Biol"},{"key":"BFsrep06922_CR12","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1099\/mic.0.048025-0","volume":"157","author":"H Agustiandari","year":"2011","unstructured":"Agustiandari, H., Peeters, E., de Wit, J. G., Charlier, D. & Driessen, A. J. LmrR-mediated gene regulation of multidrug resistance in Lactococcus lactis. Microbiology 157, 1519\u201330 (2011).","journal-title":"Microbiology"},{"key":"BFsrep06922_CR13","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/emboj.2008.263","volume":"28","author":"PK Madoori","year":"2009","unstructured":"Madoori, P. K., Agustiandari, H., Driessen, A. J. & Thunnissen, A. M. Structure of the transcriptional regulator LmrR and its mechanism of multidrug recognition. Embo j 28, 156\u201366 (2009).","journal-title":"Embo j"},{"key":"BFsrep06922_CR14","doi-asserted-by":"crossref","first-page":"7589","DOI":"10.1021\/ja102090z","volume":"132","author":"DF Hansen","year":"2010","unstructured":"Hansen, D. F., Neudecker, P. & Kay, L. E. Determination of Isoleucine Side-Chain Conformations in Ground and Excited States of Proteins from Chemical Shifts. J Am Chem Soc 132, 7589\u20137591 (2010).","journal-title":"J Am Chem Soc"},{"key":"BFsrep06922_CR15","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1002\/pro.2045","volume":"21","author":"TM Sabo","year":"2012","unstructured":"Sabo, T. M. et al. Thermal coefficients of the methyl groups within ubiquitin. Protein Sci 21, 562\u2013570 (2012).","journal-title":"Protein Sci"},{"key":"BFsrep06922_CR16","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s10858-010-9436-6","volume":"48","author":"G Butterfoss","year":"2010","unstructured":"Butterfoss, G. et al. Conformational dependence of 13C shielding and coupling constants for methionine methyl groups. J Biomol NMR 48, 31\u201347 (2010).","journal-title":"J Biomol NMR"},{"key":"BFsrep06922_CR17","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1021\/ja909294n","volume":"132","author":"DF Hansen","year":"2009","unstructured":"Hansen, D. F., Neudecker, P., Vallurupalli, P., Mulder, F. A. A. & Kay, L. E. Determination of Leu Side-Chain Conformations in Excited Protein States by NMR Relaxation Dispersion. J Am Chem Soc 132, 42\u201343 (2009).","journal-title":"J Am Chem Soc"},{"key":"BFsrep06922_CR18","doi-asserted-by":"crossref","first-page":"11097","DOI":"10.1021\/ja802729t","volume":"130","author":"RE London","year":"2008","unstructured":"London, R. E., Wingad, B. D. & Mueller, G. A. Dependence of Amino Acid Side Chain 13C Shifts on Dihedral Angle: Application to Conformational Analysis. J Am Chem Soc 130, 11097\u201311105 (2008).","journal-title":"J Am Chem Soc"},{"key":"BFsrep06922_CR19","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1038\/ncomms2046","volume":"3","author":"Y Kofuku","year":"2012","unstructured":"Kofuku, Y. et al. Efficacy of the \u03b22-adrenergic receptor is determined by conformational equilibrium in the transmembrane region. Nat Commun 3, 1045 (2012).","journal-title":"Nat Commun"},{"key":"BFsrep06922_CR20","doi-asserted-by":"crossref","first-page":"6216","DOI":"10.1073\/pnas.0911270107","volume":"107","author":"S Imai","year":"2010","unstructured":"Imai, S., Osawa, M., Takeuchi, K. & Shimada, I. Structural basis underlying the dual gate properties of KcsA. Proc Natl Acad Sci 107, 6216\u201321 (2010).","journal-title":"Proc Natl Acad Sci"},{"key":"BFsrep06922_CR21","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0959-440X(97)80028-0","volume":"7","author":"GP Brady","year":"1997","unstructured":"Brady, G. P. & Sharp, K. A. Entropy in protein folding and in protein\u2014protein interactions. Curr Opin Struct Biol 7, 215\u2013221 (1997).","journal-title":"Curr Opin Struct Biol"},{"key":"BFsrep06922_CR22","doi-asserted-by":"crossref","first-page":"14878","DOI":"10.1021\/jp209049k","volume":"115","author":"H Sun","year":"2011","unstructured":"Sun, H., Kay, L. E. & Tugarinov, V. An Optimized Relaxation-Based Coherence Transfer NMR Experiment for the Measurement of Side-Chain Order in Methyl-Protonated, Highly Deuterated Proteins. J Phys Chem B 115, 14878\u201314884 (2011).","journal-title":"J Phys Chem B"},{"key":"BFsrep06922_CR23","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1021\/ja067827z","volume":"129","author":"V Tugarinov","year":"2007","unstructured":"Tugarinov, V., Sprangers, R. & Kay, L. E. Probing Side-Chain Dynamics in the Proteasome by Relaxation Violated Coherence Transfer NMR Spectroscopy. J Am Chem Soc 129, 1743\u20131750 (2007).","journal-title":"J Am Chem Soc"},{"key":"BFsrep06922_CR24","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1042\/BST20110750","volume":"40","author":"M Akke","year":"2012","unstructured":"Akke, M. Conformational dynamics and thermodynamics of protein-ligand binding studied by NMR relaxation. Biochem Soc Trans 40, 419\u201323 (2012).","journal-title":"Biochem Soc Trans"},{"key":"BFsrep06922_CR25","doi-asserted-by":"crossref","first-page":"9832","DOI":"10.1021\/ja00074a073","volume":"115","author":"M Akke","year":"1993","unstructured":"Akke, M., Brueschweiler, R. & Palmer, A. G. NMR order parameters and free energy: an analytical approach and its application to cooperative calcium(2+) binding by calbindin D9k. J Am Chem Soc 115, 9832\u20139833 (1993).","journal-title":"J Am Chem Soc"},{"key":"BFsrep06922_CR26","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1006\/jmbi.1996.0581","volume":"263","author":"D Yang","year":"1996","unstructured":"Yang, D. & Kay, L. E. Contributions to Conformational Entropy Arising from Bond Vector Fluctuations Measured from NMR-Derived Order Parameters: Application to Protein Folding. J Mol Biol 263, 369\u2013382 (1996).","journal-title":"J Mol Biol"},{"key":"BFsrep06922_CR27","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1002\/pro.5560051228","volume":"5","author":"Z Li","year":"1996","unstructured":"Li, Z., Raychaudhuri, S. & Wand, A. J. Insights into the local residual entropy of proteins provided by NMR relaxation. Protein Sci 5, 2647\u20132650 (1996).","journal-title":"Protein Sci"},{"key":"BFsrep06922_CR28","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/nchembio.347","volume":"6","author":"MS Marlow","year":"2010","unstructured":"Marlow, M. S., Dogan, J., Frederick, K. K., Valentine, K. G. & Wand, A. J. The role of conformational entropy in molecular recognition by calmodulin. Nat Chem Biol 6, 352\u20138 (2010).","journal-title":"Nat Chem Biol"},{"key":"BFsrep06922_CR29","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nature05959","volume":"448","author":"KK Frederick","year":"2007","unstructured":"Frederick, K. K., Marlow, M. S., Valentine, K. G. & Wand, A. J. Conformational entropy in molecular recognition by proteins. Nature 448, 325\u20139 (2007).","journal-title":"Nature"},{"key":"BFsrep06922_CR30","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/nature11271","volume":"488","author":"SR Tzeng","year":"2012","unstructured":"Tzeng, S. R. & Kalodimos, C. G. Protein activity regulation by conformational entropy. Nature 488, 236\u201340 (2012).","journal-title":"Nature"},{"key":"BFsrep06922_CR31","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1002\/pro.614","volume":"20","author":"CG Kalodimos","year":"2011","unstructured":"Kalodimos, C. G. NMR reveals novel mechanisms of protein activity regulation. Protein Sci 20, 773\u201382 (2011).","journal-title":"Protein Sci"},{"key":"BFsrep06922_CR32","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/nature08560","volume":"462","author":"SR Tzeng","year":"2009","unstructured":"Tzeng, S. R. & Kalodimos, C. G. Dynamic activation of an allosteric regulatory protein. Nature 462, 368\u201372 (2009).","journal-title":"Nature"},{"key":"BFsrep06922_CR33","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1038\/nsmb1132","volume":"13","author":"N Popovych","year":"2006","unstructured":"Popovych, N., Sun, S., Ebright, R. H. & Kalodimos, C. G. Dynamically driven protein allostery. Nat Struct Mol Biol 13, 831\u20138 (2006).","journal-title":"Nat Struct Mol Biol"},{"key":"BFsrep06922_CR34","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.coph.2010.09.006","volume":"10","author":"PJ Sapienza","year":"2010","unstructured":"Sapienza, P. J. & Lee, A. L. Using NMR to study fast dynamics in proteins: methods and applications. Curr Opin Pharm 10, 723\u2013730 (2010).","journal-title":"Curr Opin Pharm"},{"key":"BFsrep06922_CR35","doi-asserted-by":"crossref","first-page":"18249","DOI":"10.1073\/pnas.0904492106","volume":"106","author":"CM Petit","year":"2009","unstructured":"Petit, C. M., Zhang, J., Sapienza, P. J., Fuentes, E. J. & Lee, A. L. Hidden dynamic allostery in a PDZ domain. Proc Natl Acad Sci 106, 18249\u201354 (2009).","journal-title":"Proc Natl Acad Sci"},{"key":"BFsrep06922_CR36","doi-asserted-by":"crossref","first-page":"13802","DOI":"10.1073\/pnas.0904005106","volume":"106","author":"A Vallee-Belisle","year":"2009","unstructured":"Vallee-Belisle, A., Ricci, F. & Plaxco, K. W. Thermodynamic basis for the optimization of binding-induced biomolecular switches and structure-switching biosensors. Proc Natl Acad Sci 106, 13802\u20137 (2009).","journal-title":"Proc Natl Acad Sci"},{"key":"BFsrep06922_CR37","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1126\/science.1157092","volume":"320","author":"OF Lange","year":"2008","unstructured":"Lange, O. F. et al. Recognition dynamics up to microseconds revealed from an RDC-derived ubiquitin ensemble in solution. Science 320, 1471\u20135 (2008).","journal-title":"Science"},{"key":"BFsrep06922_CR38","doi-asserted-by":"crossref","first-page":"15092","DOI":"10.1021\/ja405200u","volume":"135","author":"V Kasinath","year":"2013","unstructured":"Kasinath, V., Sharp, K. A. & Wand, A. J. Microscopic insights into the NMR relaxation-based protein conformational entropy meter. J Am Chem Soc 135, 15092\u2013100 (2013).","journal-title":"J Am Chem Soc"},{"key":"BFsrep06922_CR39","doi-asserted-by":"crossref","first-page":"8389","DOI":"10.1021\/ja072576v","volume":"129","author":"BE Brooks","year":"2007","unstructured":"Brooks, B. E., Piro, K. M. & Brennan, R. G. Multidrug-Binding Transcription Factor QacR Binds the Bivalent Aromatic Diamidines DB75 and DB359 in Multiple Positions. J Am Chem Soc 129, 8389\u20138395 (2007).","journal-title":"J Am Chem Soc"},{"key":"BFsrep06922_CR40","doi-asserted-by":"crossref","first-page":"6048","DOI":"10.1021\/ja809526q","volume":"131","author":"F Ferrage","year":"2009","unstructured":"Ferrage, F., Cowburn, D. & Ghose, R. Accurate Sampling of High-Frequency Motions in Proteins by Steady-State 15N\u2212{1H} Nuclear Overhauser Effect Measurements in the Presence of Cross-Correlated Relaxation. J Am Chem Soc 131, 6048\u20136049 (2009).","journal-title":"J Am Chem Soc"},{"key":"BFsrep06922_CR41","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jmr.2005.08.014","volume":"178","author":"D Lee","year":"2006","unstructured":"Lee, D., Hilty, C., Wider, G. & W\u00fcthrich, K. Effective rotational correlation times of proteins from NMR relaxation interference. J Magn Reson 178, 72\u20136 (2006).","journal-title":"J Magn Reson"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep06922.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep06922","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep06922.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T01:22:20Z","timestamp":1672968140000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep06922"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11,18]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,12,17]]}},"alternative-id":["BFsrep06922"],"URL":"https:\/\/doi.org\/10.1038\/srep06922","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725239935.793515076","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,11,18]]},"assertion":[{"value":"8 July 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 October 2014","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2014","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6922"}}