Structural basis for the blockade of MATE multidrug efflux pumps

Radchenko, Martha; Symersky, Jindrich; Nie, Rongxin; Lu, Min

doi:10.1038/ncomms8995

Structural basis for the blockade of MATE multidrug efflux pumps

Journal Article · Thu Aug 06 00:00:00 EDT 2015 · Nature Communications

DOI:https://doi.org/10.1038/ncomms8995· OSTI ID:1214707

Radchenko, Martha ^[1]; Symersky, Jindrich ^[1]; Nie, Rongxin ^[1]; Lu, Min ^[1]

Rosalind Franklin Univ. of Medicine and Sciences, North Chicago, IL (United States). Dept. of Biochemistry and Molecular Biology.

Multidrug and toxic compound extrusion (MATE) transporters underpin multidrug resistance by using the H⁺ or Na⁺ electrochemical gradient to extrude different drugs across cell membranes. MATE transporters can be further parsed into the DinF, NorM and eukaryotic subfamilies based on their amino-acid sequence similarity. Here we report the 3.0 Å resolution X-ray structures of a protonation-mimetic mutant of an H⁺-coupled DinF transporter, as well as of an H⁺-coupled DinF and a Na⁺-coupled NorM transporters in complexes with verapamil, a small-molecule pharmaceutical that inhibits MATE-mediated multidrug extrusion. Combining structure-inspired mutational and functional studies, we confirm the biological relevance of our crystal structures, reveal the mechanistic differences among MATE transporters, and suggest how verapamil inhibits MATE-mediated multidrug efflux. Our findings offer insights into how MATE transporters extrude chemically and structurally dissimilar drugs and could inform the design of new strategies for tackling multidrug resistance.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1214707

Alternate ID(s):: OSTI ID: 1245872

Journal Information:: Nature Communications, Journal Name: Nature Communications Vol. 6; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (51)

Multidrug efflux transporters in the MATE family Kuroda, Teruo; Tsuchiya, Tomofusa Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1794, Issue 5 https://doi.org/10.1016/j.bbapap.2008.11.012	journal	May 2009
Practical applications and feasibility of efflux pump inhibitors in the clinic—A vision for applied use Lomovskaya, Olga; Bostian, Keith A. Biochemical Pharmacology, Vol. 71, Issue 7 https://doi.org/10.1016/j.bcp.2005.12.008	journal	March 2006
The MATE proteins as fundamental transporters of metabolic and xenobiotic organic cations Omote, Hiroshi; Hiasa, Miki; Matsumoto, Takuya Trends in Pharmacological Sciences, Vol. 27, Issue 11 https://doi.org/10.1016/j.tips.2006.09.001	journal	November 2006
A structure-based mechanism for drug binding by multidrug transporters Zheleznova, Ekaterina E.; Markham, Penelope; Edgar, Rotem Trends in Biochemical Sciences, Vol. 25, Issue 2 https://doi.org/10.1016/s0968-0004(99)01514-5	journal	February 2000
Na ⁺ –Substrate Coupling in the Multidrug Antiporter NorM Probed with a Spin-Labeled Substrate Steed, P. Ryan; Stein, Richard A.; Mishra, Smriti Biochemistry, Vol. 52, Issue 34 https://doi.org/10.1021/bi4008935	journal	August 2013
Structure of a cation-bound multidrug and toxic compound extrusion transporter He, Xiao; Szewczyk, Paul; Karyakin, Andrey Nature, Vol. 467, Issue 7318 https://doi.org/10.1038/nature09408	journal	September 2010
Structural basis for the inhibition of bacterial multidrug exporters Nakashima, Ryosuke; Sakurai, Keisuke; Yamasaki, Seiji Nature, Vol. 500, Issue 7460, p. 102-106 https://doi.org/10.1038/nature12300	journal	June 2013
Export of a single drug molecule in two transport cycles by a multidrug efflux pump Fluman, Nir; Adler, Julia; Rotenberg, Susan A. Nature Communications, Vol. 5, Issue 1 https://doi.org/10.1038/ncomms5615	journal	August 2014
Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances Wiegand, Irith; Hilpert, Kai; Hancock, Robert E. W. Nature Protocols, Vol. 3, Issue 2 https://doi.org/10.1038/nprot.2007.521	journal	January 2008
Structural insights into H+-coupled multidrug extrusion by a MATE transporter Lu, Min; Radchenko, Martha; Symersky, Jindrich Nature Structural & Molecular Biology, Vol. 20, Issue 11 https://doi.org/10.1038/nsmb.2687	journal	October 2013
Author Correction: Structural basis for the drug extrusion mechanism by a MATE multidrug transporter Tanaka, Yoshiki; Hipolito, Christopher J.; Maturana, Andrés D. Nature, Vol. 578, Issue 7794 https://doi.org/10.1038/s41586-019-1762-6	journal	January 2020
Competence-specific induction ofrecAis required for full recombination proficiency during transformation inStreptococcus pneumoniae Mortier-Barrière, Isabelle; de Saizieu, Antoine; Claverys, Jean-Pierre Molecular Microbiology, Vol. 27, Issue 1 https://doi.org/10.1046/j.1365-2958.1998.00668.x	journal	January 1998
Structures of a Na+-coupled, substrate-bound MATE multidrug transporter Lu, M.; Symersky, J.; Radchenko, M. Proceedings of the National Academy of Sciences, Vol. 110, Issue 6 https://doi.org/10.1073/pnas.1219901110	journal	January 2013
The electrochemical gradient of protons and its relationship to active transport in Escherichia coli membrane vesicles. Ramos, S.; Schuldiner, S.; Kaback, H. R. Proceedings of the National Academy of Sciences, Vol. 73, Issue 6 https://doi.org/10.1073/pnas.73.6.1892	journal	June 1976
Multidrug Transport Protein NorM from Vibrio cholerae Simultaneously Couples to Sodium- and Proton-Motive Force Jin, Yoonhee; Nair, Asha; van Veen, Hendrik W. Journal of Biological Chemistry, Vol. 289, Issue 21 https://doi.org/10.1074/jbc.m113.546770	journal	April 2014
The multidrug-resistance-reverser verapamil interferes with cellular P-glycoprotein-mediated pumping of daunorubicin as a non-competing substrate Spoelstra, Ellen C.; Westerhoff, Hans V.; Pinedo, Herbert M. European Journal of Biochemistry, Vol. 221, Issue 1 https://doi.org/10.1111/j.1432-1033.1994.tb18748.x	journal	April 1994
Structure of the Get3 targeting factor in complex with its membrane protein cargo Mateja, A.; Paduch, M.; Chang, H. -Y. Science, Vol. 347, Issue 6226 https://doi.org/10.1126/science.1261671	journal	March 2015
Functional Cloning and Characterization of the Multidrug Efflux Pumps NorM from Neisseria gonorrhoeae and YdhE from Escherichia coli Long, F.; Rouquette-Loughlin, C.; Shafer, W. M. Antimicrobial Agents and Chemotherapy, Vol. 52, Issue 9 https://doi.org/10.1128/aac.00475-08	journal	June 2008
A MATE Family Multidrug Efflux Transporter Pumps out Fluoroquinolones in Bacteroides thetaiotaomicron Miyamae, S.; Ueda, O.; Yoshimura, F. Antimicrobial Agents and Chemotherapy, Vol. 45, Issue 12 https://doi.org/10.1128/aac.45.12.3341-3346.2001	journal	December 2001
AbeM, an H+-Coupled Acinetobacter baumannii Multidrug Efflux Pump Belonging to the MATE Family of Transporters Su, X. -Z.; Chen, J.; Mizushima, T. Antimicrobial Agents and Chemotherapy, Vol. 49, Issue 10 https://doi.org/10.1128/aac.49.10.4362-4364.2005	journal	September 2005
MacAB Is Involved in the Secretion of Escherichia coli Heat-Stable Enterotoxin II Yamanaka, H.; Kobayashi, H.; Takahashi, E. Journal of Bacteriology, Vol. 190, Issue 23 https://doi.org/10.1128/jb.00853-08	journal	September 2008
An H+-Coupled Multidrug Efflux Pump, PmpM, a Member of the MATE Family of Transporters, from Pseudomonas aeruginosa He, G. -X.; Kuroda, T.; Mima, T. Journal of Bacteriology, Vol. 186, Issue 1 https://doi.org/10.1128/jb.186.1.262-265.2004	journal	December 2003
Interaction of Verapamil with Lipid Membranes and P-Glycoprotein: Connecting Thermodynamics and Membrane Structure with Functional Activity Meier, M.; Blatter, X. Li; Seelig, A. Biophysical Journal, Vol. 91, Issue 8 https://doi.org/10.1529/biophysj.106.089581	journal	October 2006
Functional Characteristics of Two Human MATE Transporters: Kinetics of Cimetidine Transport and Profiles of Iinhibition by Various Compounds Ohta, Kin-ya; Inoue, Katsuhisa; Yasujima, Tomoya Journal of Pharmacy & Pharmaceutical Sciences, Vol. 12, Issue 3 https://doi.org/10.18433/j3r59x	journal	September 2009
Antibiotics for Emerging Pathogens Agarwal, Vinayak; Nair, Satish K. Infectious Diseases https://doi.org/10.1007/978-1-4614-5719-0_2	book	December 2012
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
A structure-based mechanism for drug binding by multidrug transporters Zheleznova, Ekaterina E.; Markham, Penelope; Edgar, Rotem Trends in Biochemical Sciences, Vol. 25, Issue 2 https://doi.org/10.1016/S0968-0004(99)01514-5	journal	February 2000
Electrostatic activation of Escherichia coli methionine repressor Phillips, Kathryn; Phillips, Simon EV Structure, Vol. 2, Issue 4 https://doi.org/10.1016/S0969-2126(00)00032-0	journal	April 1994
Last of the multidrug transporters van Veen, Hendrik W. Nature, Vol. 467, Issue 7318 https://doi.org/10.1038/467926a	journal	October 2010
Multiple molecular mechanisms for multidrug resistance transporters Higgins, Christopher F. Nature, Vol. 446, Issue 7137 https://doi.org/10.1038/nature05630	journal	April 2007
Conformational entropy in molecular recognition by proteins Frederick, Kendra King; Marlow, Michael S.; Valentine, Kathleen G. Nature, Vol. 448, Issue 7151 https://doi.org/10.1038/nature05959	journal	July 2007
Structural basis for the drug extrusion mechanism by a MATE multidrug transporter Tanaka, Yoshiki; Hipolito, Christopher J.; Maturana, Andrés D. Nature, Vol. 496, Issue 7444 https://doi.org/10.1038/nature12014	journal	March 2013
Long-range electrostatic interaction in the bacterial photosynthetic reaction centre Maróti, Péter; Hanson, Deborah K.; Schiffer, Marianne Nature Structural & Molecular Biology, Vol. 2, Issue 12 https://doi.org/10.1038/nsb1295-1057	journal	December 1995
The multidrug efflux protein NorM is a prototype of a new family of transporters Brown, Melissa H.; Paulsen, Ian T.; Skurray, Ronald A. Molecular Microbiology, Vol. 31, Issue 1 https://doi.org/10.1046/j.1365-2958.1999.01162.x	journal	January 1999
A human transporter protein that mediates the final excretion step for toxic organic cations Otsuka, M.; Matsumoto, T.; Morimoto, R. Proceedings of the National Academy of Sciences, Vol. 102, Issue 50 https://doi.org/10.1073/pnas.0506483102	journal	December 2005
Functional Cloning and Characterization of a Plant Efflux Carrier for Multidrug and Heavy Metal Detoxification Li, Legong; He, Zengyong; Pandey, Girdhar K. Journal of Biological Chemistry, Vol. 277, Issue 7 https://doi.org/10.1074/jbc.M108777200	journal	December 2001
Multidrug Transport Protein NorM from Vibrio cholerae Simultaneously Couples to Sodium- and Proton-Motive Force Jin, Yoonhee; Nair, Asha; van Veen, Hendrik W. Journal of Biological Chemistry, Vol. 289, Issue 21 https://doi.org/10.1074/jbc.M113.546770	journal	April 2014
A membrane-embedded glutamate is required for ligand binding to the multidrug transporter EmrE Muth, T. R.; Schuldiner, S. The EMBO Journal, Vol. 19, Issue 2 https://doi.org/10.1093/emboj/19.2.234	journal	January 2000
Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy Mahamoud, Abdallah; Chevalier, Jacqueline; Alibert-Franco, Sandrine Journal of Antimicrobial Chemotherapy, Vol. 59, Issue 6 https://doi.org/10.1093/jac/dkl493	journal	January 2007
Improved methods for building protein models in electron density maps and the location of errors in these models Jones, T. A.; Zou, J. Y.; Cowan, S. W. Acta Crystallographica Section A Foundations of Crystallography, Vol. 47, Issue 2, p. 110-119 https://doi.org/10.1107/S0108767390010224	journal	March 1991
The CCP4 suite programs for protein crystallography No authors listed Acta Crystallographica Section D Biological Crystallography, Vol. 50, Issue 5, p. 760-763 https://doi.org/10.1107/S0907444994003112	journal	September 1994
The Proton Electrochemical Gradient in Escherichia coli Cells Padan, Etana; Zilberstein, Dan; Rottenberg, Hagai European Journal of Biochemistry, Vol. 63, Issue 2 https://doi.org/10.1111/j.1432-1033.1976.tb10257.x	journal	April 1976
Antibiotics for Emerging Pathogens Fischbach, M. A.; Walsh, C. T. Science, Vol. 325, Issue 5944 https://doi.org/10.1126/science.1176667	journal	August 2009
Functional Cloning and Characterization of the Multidrug Efflux Pumps NorM from Neisseria gonorrhoeae and YdhE from Escherichia coli Long, F.; Rouquette-Loughlin, C.; Shafer, W. M. Antimicrobial Agents and Chemotherapy, Vol. 52, Issue 9 https://doi.org/10.1128/AAC.00475-08	journal	June 2008
A MATE Family Multidrug Efflux Transporter Pumps out Fluoroquinolones in Bacteroides thetaiotaomicron Miyamae, S.; Ueda, O.; Yoshimura, F. Antimicrobial Agents and Chemotherapy, Vol. 45, Issue 12 https://doi.org/10.1128/AAC.45.12.3341-3346.2001	journal	December 2001
Characterization of emeA, a norA Homolog and Multidrug Resistance Efflux Pump, in Enterococcus faecalis Jonas, B. M.; Murray, B. E.; Weinstock, G. M. Antimicrobial Agents and Chemotherapy, Vol. 45, Issue 12 https://doi.org/10.1128/AAC.45.12.3574-3579.2001	journal	December 2001
AbeM, an H+-Coupled Acinetobacter baumannii Multidrug Efflux Pump Belonging to the MATE Family of Transporters Su, X. -Z.; Chen, J.; Mizushima, T. Antimicrobial Agents and Chemotherapy, Vol. 49, Issue 10 https://doi.org/10.1128/AAC.49.10.4362-4364.2005	journal	September 2005
MacAB Is Involved in the Secretion of Escherichia coli Heat-Stable Enterotoxin II Yamanaka, H.; Kobayashi, H.; Takahashi, E. Journal of Bacteriology, Vol. 190, Issue 23 https://doi.org/10.1128/JB.00853-08	journal	September 2008
An H+-Coupled Multidrug Efflux Pump, PmpM, a Member of the MATE Family of Transporters, from Pseudomonas aeruginosa He, G. -X.; Kuroda, T.; Mima, T. Journal of Bacteriology, Vol. 186, Issue 1 https://doi.org/10.1128/JB.186.1.262-265.2004	journal	December 2003
Identification and Functional Characterization of a New Human Kidney–Specific H ⁺ /Organic Cation Antiporter, Kidney-Specific Multidrug and Toxin Extrusion 2 Masuda, Satohiro; Terada, Tomohiro; Yonezawa, Atsushi Journal of the American Society of Nephrology, Vol. 17, Issue 8 https://doi.org/10.1681/ASN.2006030205	journal	June 2006
Functional Characteristics of Two Human MATE Transporters: Kinetics of Cimetidine Transport and Profiles of Iinhibition by Various Compounds Ohta, Kin-ya; Inoue, Katsuhisa; Yasujima, Tomoya Journal of Pharmacy & Pharmaceutical Sciences, Vol. 12, Issue 3 https://doi.org/10.18433/J3R59X	journal	September 2009

Cited By (18)

Pacing across the membrane: the novel PACE family of efflux pumps is widespread in Gram-negative pathogens Hassan, Karl A.; Liu, Qi; Elbourne, Liam D. H. Research in Microbiology, Vol. 169, Issue 7-8 https://doi.org/10.1016/j.resmic.2018.01.001	journal	September 2018
Structural basis for xenobiotic extrusion by eukaryotic MATE transporter Miyauchi, Hirotake; Moriyama, Satomi; Kusakizako, Tsukasa Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-01541-0	journal	November 2017
Structure of an engineered multidrug transporter MdfA reveals the molecular basis for substrate recognition Wu, Hsin-Hui; Symersky, Jindrich; Lu, Min Communications Biology, Vol. 2, Issue 1 https://doi.org/10.1038/s42003-019-0446-y	journal	June 2019
Structures of multidrug and toxic compound extrusion transporters and their mechanistic implications Lu, Min Channels, Vol. 10, Issue 2 https://doi.org/10.1080/19336950.2015.1106654	journal	January 2016
The putative drug efflux systems of the Bacillus cereus group Hassan, Karl A.; Fagerlund, Annette; Elbourne, Liam D. H. PLOS ONE, Vol. 12, Issue 5 https://doi.org/10.1371/journal.pone.0176188	journal	May 2017
Genomic and phenotypic characterisation of fluoroquinolone resistance mechanisms in Enterobacteriaceae in Durban, South Africa Osei Sekyere, John; Amoako, Daniel Gyamfi PLOS ONE, Vol. 12, Issue 6 https://doi.org/10.1371/journal.pone.0178888	journal	June 2017
Carbonyl Cyanide m-Chlorophenylhydrazine (CCCP) Reverses Resistance to Colistin, but Not to Carbapenems and Tigecycline in Multidrug-Resistant Enterobacteriaceae Osei Sekyere, John; Amoako, Daniel G. Frontiers in Microbiology, Vol. 8 https://doi.org/10.3389/fmicb.2017.00228	journal	February 2017
Efflux pump inhibitors for bacterial pathogens: From bench to bedside Pathania, Ranjana; Sharma, Atin; Gupta, VivekKumar Indian Journal of Medical Research, Vol. 149, Issue 2 https://doi.org/10.4103/ijmr.ijmr_2079_17	journal	January 2019
Lipid Flippases for Bacterial Peptidoglycan Biosynthesis Ruiz, Natividad Lipid Insights, Vol. 8s1 https://doi.org/10.4137/lpi.s31783	journal	January 2015
Multidrug efflux pumps: structure, function and regulation Du, Dijun; Wang-Kan, Xuan; Neuberger, Arthur Nature Reviews Microbiology, Vol. 16, Issue 9 https://doi.org/10.1038/s41579-018-0048-6	journal	July 2018
Functional characterization and discovery of modulators of SbMATE, the agronomically important aluminium tolerance transporter from Sorghum bicolor Doshi, Rupak; McGrath, Aaron P.; Piñeros, Miguel Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-18146-8	journal	December 2017
Broadly conserved Na ⁺ -binding site in the N-lobe of prokaryotic multidrug MATE transporters Ficici, Emel; Zhou, Wenchang; Castellano, Steven Proceedings of the National Academy of Sciences, Vol. 115, Issue 27 https://doi.org/10.1073/pnas.1802080115	journal	June 2018
Sodium and proton coupling in the conformational cycle of a MATE antiporter from Vibrio cholerae Claxton, Derek P.; Jagessar, Kevin L.; Steed, P. Ryan Proceedings of the National Academy of Sciences, Vol. 115, Issue 27 https://doi.org/10.1073/pnas.1802417115	journal	June 2018
Inward-facing conformation of a multidrug resistance MATE family transporter Zakrzewska, Sandra; Mehdipour, Ahmad Reza; Malviya, Viveka Nand Proceedings of the National Academy of Sciences, Vol. 116, Issue 25 https://doi.org/10.1073/pnas.1904210116	journal	June 2019
The N-terminal domain of an archaeal multidrug and toxin extrusion (MATE) transporter mediates proton coupling required for prokaryotic drug resistance Jagessar, Kevin L.; Mchaourab, Hassane S.; Claxton, Derek P. Journal of Biological Chemistry, Vol. 294, Issue 34 https://doi.org/10.1074/jbc.ra119.009195	journal	July 2019
Tackling drug resistance with efflux pump inhibitors: from bacteria to cancerous cells Lowrence, Rene Christena; Subramaniapillai, Selva Ganesan; Ulaganathan, Venkatasubramanian Critical Reviews in Microbiology, Vol. 45, Issue 3 https://doi.org/10.1080/1040841x.2019.1607248	journal	April 2019
The multitasking abilities of MATE transporters in plants Upadhyay, Neha; Kar, Debojyoti; Deepak Mahajan, Bhagyashri Journal of Experimental Botany, Vol. 70, Issue 18 https://doi.org/10.1093/jxb/erz246	journal	May 2019
Functional characterization and discovery of modulators of SbMATE, the agronomically important aluminium tolerance transporter from Sorghum bicolor Doshi, Rupak; McGrath, Aaron P.; Pineros, Miguel Scientific Reports https://doi.org/10.1101/182964	journal	August 2017

Similar Records

Structures and transport dynamics of a Campylobacter jejuni multidrug efflux pump

Journal Article · Tue Aug 01 00:00:00 EDT 2017 · Nature Communications · OSTI ID:1377903

Structure of a cation-bound multidrug and toxic compound extrusion transporter

Journal Article · Tue Oct 26 00:00:00 EDT 2010 · Nature · OSTI ID:1002815

Crystallization and preliminary X-ray diffraction analysis of the multidrug efflux transporter NorM from Neisseria gonorrhoeae

Journal Article · Tue Apr 01 00:00:00 EDT 2008 · Acta Crystallographica. Section F · OSTI ID:22360519

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
biochemistry
biological sciences
biophysics

Structural basis for the blockade of MATE multidrug efflux pumps

Citation Formats

References (51)

Cited By (18)

Similar Records

Related Subjects