7p04 › Citations

Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5.

<div class='caption-title'>Structural features of Pdr5.</div>
<div class='caption-title'>Structural comparison of Pdr5 and related transporters.</div>
<div class='caption-title'>Structure of Pdr5 linker domain.</div>
Harris A, Wagner M, Du D, Raschka S, Nentwig LM, Gohlke H, Smits SHJ, Luisi BF, Schmitt L
OpenAccess logo Nat Commun 12 5254 (2021)
Related entries: 7p03, 7p05, 7p06

Cited: 22 times
EuropePMC logo PMID: 34489436

Abstract

Pdr5, a member of the extensive ABC transporter superfamily, is representative of a clinically relevant subgroup involved in pleiotropic drug resistance. Pdr5 and its homologues drive drug efflux through uncoupled hydrolysis of nucleotides, enabling organisms such as baker's yeast and pathogenic fungi to survive in the presence of chemically diverse antifungal agents. Here, we present the molecular structure of Pdr5 solved with single particle cryo-EM, revealing details of an ATP-driven conformational cycle, which mechanically drives drug translocation through an amphipathic channel, and a clamping switch within a conserved linker loop that acts as a nucleotide sensor. One half of the transporter remains nearly invariant throughout the cycle, while its partner undergoes changes that are transmitted across inter-domain interfaces to support a peristaltic motion of the pumped molecule. The efflux model proposed here rationalises the pleiotropic impact of Pdr5 and opens new avenues for the development of effective antifungal compounds.

Articles - 7p04 mentioned but not cited (1)

  1. Restriction of access to the central cavity is a major contributor to substrate selectivity in plant ABCG transporters. Pakuła K, Sequeiros-Borja C, Biała-Leonhard W, Pawela A, Banasiak J, Bailly A, Radom M, Geisler M, Brezovsky J, Jasiński M. Cell Mol Life Sci 80 105 (2023)


Reviews citing this publication (6)

  1. Multidrug Resistance in Mammals and Fungi-From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms. Khunweeraphong N, Kuchler K. Int J Mol Sci 22 4806 (2021)
  2. Snapshots of ABCG1 and ABCG5/G8: A Sterol's Journey to Cross the Cellular Membranes. Rezaei F, Farhat D, Gursu G, Samnani S, Lee JY. Int J Mol Sci 24 484 (2022)
  3. CryoEM Data Analysis of Membrane Proteins. Practical Considerations on Amphipathic Belts, Ligands, and Variability Analysis. Gobet A, Moissonnier L, Chaptal V. Methods Mol Biol 2715 471-483 (2024)
  4. Fungal Drug Response and Antimicrobial Resistance. Osset-Trénor P, Pascual-Ahuir A, Proft M. J Fungi (Basel) 9 565 (2023)
  5. Interaction of Vanadium Complexes with Proteins: Revisiting the Reported Structures in the Protein Data Bank (PDB) since 2015. Santos MFA, Pessoa JC. Molecules 28 6538 (2023)
  6. Recent advances in membrane mimetics for membrane protein research. Young JW. Biochem Soc Trans 51 1405-1416 (2023)

Articles citing this publication (15)

  1. Biosynthesis of tetrahydropapaverine and semisynthesis of papaverine in yeast. Jamil OK, Cravens A, Payne JT, Kim CY, Smolke CD. Proc Natl Acad Sci U S A 119 e2205848119 (2022)
  2. Cryo-EM structures of human ABCA7 provide insights into its phospholipid translocation mechanisms. Le LTM, Thompson JR, Dehghani-Ghahnaviyeh S, Pant S, Dang PX, French JB, Kanikeyo T, Tajkhorshid E, Alam A. EMBO J 42 e111065 (2023)
  3. A Chemogenomic Toolkit to Evaluate the "Ins and Outs" of Yeast Plasma Membrane Transporters. Prasad R, Banerjee A. mBio 13 e0095522 (2022)
  4. Engineering Saccharomyces cerevisiae for enhanced (-)-α-bisabolol production. Jiang Y, Xia L, Gao S, Li N, Yu S, Zhou J. Synth Syst Biotechnol 8 187-195 (2023)
  5. Gene-by-environment interactions are pervasive among natural genetic variants. Chen SA, Kern AF, Ang RML, Xie Y, Fraser HB. Cell Genom 3 100273 (2023)
  6. Genomic Data Mining Reveals Abundant Uncharacterized Transporters in Coccidioides immitis and Coccidioides posadasii. Cai H, Zhang H, Guo DH, Wang Y, Gu J. J Fungi (Basel) 8 1064 (2022)
  7. Identification of novel plant cysteine oxidase inhibitors from a yeast chemical genetic screen. Lavilla-Puerta M, Latter R, Bellè F, Cervelli T, Galli A, Perata P, Chini A, Flashman E, Giuntoli B. J Biol Chem 299 105366 (2023)
  8. Inhibitor-Resistant Mutants Give Important Insights into Candida albicans ABC Transporter Cdr1 Substrate Specificity and Help Elucidate Efflux Pump Inhibition. Niimi M, Niimi K, Tanabe K, Cannon RD, Lamping E. Antimicrob Agents Chemother 66 e0174821 (2022)
  9. Residues forming the gating regions of asymmetric multidrug transporter Pdr5 also play roles in conformational switching and protein folding. Alhumaidi M, Nentwig LM, Rahman H, Schmitt L, Rudrow A, Harris A, Dillon C, Restrepo L, Lamping E, Arya N, Ambudkar SV, Choy JS, Golin J. J Biol Chem 298 102689 (2022)
  10. Role of nanostructured lipid carriers in the expression alterations of ATP-binding cassette transporter genes in fluconazole-resistant Candida glabrata. Moazeni M, Saeedi M, Kelidari H, Roohi B, Hedayati MT, Shokohi T, Nabili M, Asare-Addo K, Nokhodchi A. Bioimpacts 12 561-566 (2022)
  11. Structural basis for abscisic acid efflux mediated by ABCG25 in Arabidopsis thaliana. Ying W, Liao L, Wei H, Gao Y, Liu X, Sun L. Nat Plants 9 1697-1708 (2023)
  12. Structures of channelrhodopsin paralogs in peptidiscs explain their contrasting K+ and Na+ selectivities. Morizumi T, Kim K, Li H, Govorunova EG, Sineshchekov OA, Wang Y, Zheng L, Bertalan É, Bondar AN, Askari A, Brown LS, Spudich JL, Ernst OP. Nat Commun 14 4365 (2023)
  13. UME6 Is Involved in the Suppression of Basal Transcription of ABC Transporters and Drug Resistance in the ρ+ Cells of Saccharomyces cerevisiae. Yamada Y. Microorganisms 10 601 (2022)
  14. Variations in exons 11 and 12 of the multi-pest resistance wheat gene Lr34 are independently additive for leaf rust resistance. Cloutier S, Reimer E, Khadka B, McCallum BD. Front Plant Sci 13 1061490 (2022)
  15. Yeast as a tool for membrane protein production and structure determination. Carlesso A, Delgado R, Ruiz Isant O, Uwangue O, Valli D, Bill RM, Hedfalk K. FEMS Yeast Res 22 foac047 (2022)


Quick links