Crystal Structure of a Plant Multidrug and Toxic Compound Extrusion Family Protein

Tanaka, Yoshiki; Iwaki, Shigehiro; Tsukazaki, Tomoya

doi:10.1016/j.str.2017.07.009

Cited by 44 publications

(38 citation statements)

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“…Thus, the central cleft between the N-and C-lobes is closed on the intracellular side. These structural features of VcmN are also observed in other previously reported MATE transporter structures (Miyauchi et al, 2017;Tanaka et al, 2013Tanaka et al, , 2017He et al, 2010;Lu et al, 2013aLu et al, , 2013bMousa et al, 2016;Radchenko et al, 2015).…”

Section: Overall Structures Of Vcmnsupporting

confidence: 86%

“…the NorM, DinF, and eukaryotic subfamilies (Omote et al, 2006). Over the last decade, structural and biochemical analyses of MATE transporters have been intensively pursued (Miyauchi et al, 2017;Tanaka et al, 2013Tanaka et al, , 2017He et al, 2010;Lu et al, 2013aLu et al, , 2013bMousa et al, 2016;Radchenko et al, 2015). To date, the crystal structures of five prokaryotic MATE transporters have been reported: Vibrio cholerae NorM subfamily (NorM-VC) (He et al, 2010) simultaneously coupled to the Na + and H + gradients (Jin et al, 2014), two Na + -driven MATE transporters (Neisseria gonorrhoeae NorM [NorM-NG] [Lu et al, 2013a] and Escherichia coli DinF subfamilies [ClbM] [Mousa et al, 2016]), and two H + -driven MATE transporters (Pyrococcus furiosus DinF [PfMATE] and Bacillus halodurans DinF subfamilies [DinF-BH] [Lu et al, 2013b;Radchenko et al, 2015]).…”

Section: Introductionmentioning

confidence: 99%

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Structural Basis of H+-Dependent Conformational Change in a Bacterial MATE Transporter

et al. 2019

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Graphical Abstract Highlights d Crystal structures of VcmN, an H + -coupled MATE transporter from Vibrio cholerae d Distinct conformations associated with different pHs and the D35N mutation in TM1 d Coupling of rearrangement of hydrogen bond network around Asp35 to the TM1 bending d Common step in the transport cycle shared among prokaryotic H + -driven MATE proteins SUMMARY Multidrug and toxic compound extrusion (MATE) transporters efflux toxic compounds using a Na + or H + gradient across the membrane. Although the structures of MATE transporters have been reported, the cation-coupled substrate transport mechanism remains controversial. Here we report crystal structures of VcmN, a Vibrio cholerae MATE transporter driven by the H + gradient. High-resolution structures in two distinct conformations associated with different pHs revealed that the rearrangement of the hydrogen-bonding network around the conserved Asp35 induces the bending of transmembrane helix 1, as in the case of the H + -coupled Pyrococcus furiosus MATE transporter. We also determined the crystal structure of the D35N mutant, which captured a unique conformation of TM1 facilitated by an altered hydrogen-bonding network. Based on the present results, we propose a common step in the transport cycle shared among prokaryotic H + -coupled MATE transporters.

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Section: Overall Structures Of Vcmnsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Structural Basis of H+-Dependent Conformational Change in a Bacterial MATE Transporter

et al. 2019

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“…Based on their amino acid sequence similarity, the MATE family members are classified into the NorM, the DNA damage-inducible protein F (DinF), and the eukaryotic subfamilies (2). In recent years, the crystal structures of representative members of all three subfamilies have been published (7)(8)(9)(10)(11)(12)(13)(14)(15). Since all of them represent only an outward-facing state, a detailed understanding of the complete transport cycle has remained elusive.…”

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confidence: 99%

Inward-facing conformation of a multidrug resistance MATE family transporter

Zakrzewska

Mehdipour

Malviya

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Multidrug and toxic compound extrusion (MATE) transporters mediate excretion of xenobiotics and toxic metabolites, thereby conferring multidrug resistance in bacterial pathogens and cancer cells. Structural information on the alternate conformational states and knowledge of the detailed mechanism of MATE transport are of great importance for drug development. However, the structures of MATE transporters are only known in V-shaped outward-facing conformations. Here, we present the crystal structure of a MATE transporter from Pyrococcus furiosus (PfMATE) in the long-soughtafter inward-facing state, which was obtained after crystallization in the presence of native lipids. Transition from the outward-facing state to the inward-facing state involves rigid body movements of transmembrane helices (TMs) 2-6 and 8-12 to form an inverted V, facilitated by a loose binding of TM1 and TM7 to their respective bundles and their conformational flexibility. The inward-facing structure of PfMATE in combination with the outward-facing one supports an alternating access mechanism for the MATE family transporters. multidrug resistance | membrane protein structure | MATE transporter | inward-facing conformation | lipids

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“…Until very recently, the canon of MATE structures was limited to outward-facing (OF) conformations in which the two lobes, related by an intramolecular two-fold symmetry and connected by a cytoplasmic loop, diverge and orient away from each other near the middle of the membrane forming a large central cavity open to the extracellular side [16][17][18][19][20][21][22][23] . Crystal structures of a NorM transporter from N. gonorrheae, NorM-Ng, bound to tetraphenylphosphonium, ethidium, and rhodamine 6G (R6G) demonstrated that substrates can bind to the same location within the central cavity between the two lobes 18 .…”

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confidence: 99%

Sequence and Structural Determinants of Ligand-dependent Alternating Access of a MATE Transporter

Jagessar

Claxton

Mchaourab

2019

Preprint

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MATE transporters are ubiquitous ion-coupled antiporters that extrude structurally-and chemically-dissimilar molecules and have been implicated in conferring multidrug resistance.Here, we integrate Double Electron Electron Resonance (DEER) in conjunction with functional assays and site-directed mutagenesis of conserved residues to illuminate principles of liganddependent alternating access of PfMATE, a proton-coupled MATE from the hyperthermophilic archaeon Pyrococcus furiosus. Pairs of spin labels monitoring the two sides of the transporter reconstituted into nanodiscs reveal large amplitude movement of helices that alter the orientation of a putative substrate binding cavity. We found that acidic pH favors formation of an inwardfacing (IF) conformation, whereas elevated pH (>7) and the substrate rhodamine 6G stabilizes an outward-facing (OF) conformation. PfMATE isomerization between outward-facing and inwardfacing conformations is driven by protonation of a previously unidentified intracellular glutamate residue that is critical for drug resistance. Our results can be framed in a mechanistic model of transport that addresses central aspects of ligand coupling and alternating access.

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Crystal Structure of a Plant Multidrug and Toxic Compound Extrusion Family Protein

Cited by 44 publications

References 44 publications

Structural Basis of H+-Dependent Conformational Change in a Bacterial MATE Transporter

Structural Basis of H+-Dependent Conformational Change in a Bacterial MATE Transporter

Inward-facing conformation of a multidrug resistance MATE family transporter

Sequence and Structural Determinants of Ligand-dependent Alternating Access of a MATE Transporter

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