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The ATP switch model for ABC transporters

Nature Structural & Molecular Biology volume 11, pages 918–926 (2004)Cite this article

Abstract

ABC transporters mediate active translocation of a diverse range of molecules across all cell membranes. They comprise two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs). Recent biochemical, structural and genetic studies have led to the ATP-switch model in which ATP binding and ATP hydrolysis, respectively, induce formation and dissociation of an NBD dimer. This provides an exquisitely regulated switch that induces conformational changes in the TMDs to mediate membrane transport.

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Figure 1: Schematic representation of the vitamin B12 transporter BtuCD of E. coli (PDB entry 1L7V)12.
Figure 2: Structure of the NBDs of ABC transporters.
Figure 3: The ATP switch model for the transport cycle of an ABC transporter.

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References

  1. Holland, I.B., Cole, S.P.C., Kuchler, K. & Higgins, C.F. ABC Proteins: From Bacteria to Man (Academic, London, 2003).

    Google Scholar 

  2. Higgins, C.F. et al. Complete nucleotide sequence and identification of membrane components of the histidine transport operon of S. typhimurium. Nature 298, 723–727 (1982).

    CAS  Google Scholar 

  3. Higgins, C.F. et al. A family of related ATP-binding subunits coupled to many distinct biological processes in bacteria. Nature 323, 448–450 (1986).

    CAS  Google Scholar 

  4. Hobson, A.C., Weatherwax, R. & Ames, G.F.-L. ATP-binding sites in the membrane components of histidine permease, a periplasmic transport system. Proc. Natl. Acad. Sci. USA 81, 7333–7337 (1984).

    CAS  PubMed  Google Scholar 

  5. Higgins, C.F., Hiles, I.D., Whalley, K. & Jamieson, D.J. Nucleotide binding by membrane components of bacterial periplasmic binding protein-dependent transport systems. EMBO J. 4, 1033–1040 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Bishop, L., Agbayani, R., Ambudkar, S.V., Maloney, P.C. & Ames, G.F.-L. Reconstitution of a bacterial periplasmic permease in proteoliposomes and demonstration of ATP hydrolysis concomitant with transport. Proc. Natl. Acad. Sci. USA 86, 6953–6957 (1989).

    CAS  PubMed  Google Scholar 

  7. Mimmack, M.L., et al. Energy coupling to periplasmic binding protein-dependent transport systems: stoichiometry of ATP hydrolysis during transport in vivo. Proc. Natl. Acad. Sci. USA 86, 8257–8261 (1989).

    CAS  PubMed  Google Scholar 

  8. Hopfner, K.-P. et al. Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase. Cell 101, 789–800 (2000).

    CAS  Google Scholar 

  9. Smith, P.C. et al. ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer. Mol. Cell 10, 139–149 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lamers, M.H. et al. The crystal structure of DNA mismatch repair protein MutS binding to a G x T mismatch. Nature 407, 711–717 (2000).

    CAS  Google Scholar 

  11. Obmolova, G., Ban, C., Hsieh, P. & Yang, W. Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA. Nature, 407, 703–710 (2000).

    CAS  Google Scholar 

  12. Locher, K.P., Lee, A.T. & Rees, D.C. The E. coli BtuCD structure: a framework for ABC transporter architecture and mechanism. Science 296, 1091–1098 (2002).

    CAS  Google Scholar 

  13. Rosenberg, M.F., Callaghan, R., Ford, R.C. & Higgins, C.F. Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis. J. Biol. Chem. 272, 10685–10694 (1997).

    CAS  Google Scholar 

  14. Rosenberg, M.F. et al. Repacking of the transmembrane domains of P-glycoprotein during the transport ATPase cycle. EMBO J. 20, 5615–5625 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Rosenberg, M.F., Kamis, A.B., Callaghan, R. & Higgins, C.F. Three-dimensional structures of the mammalian multidrug resistance P-glycoprotein demonstrate major conformational changes in the transmembrane domains upon nucleotide binding. J. Biol. Chem. 278, 8294–8299 (2003).

    CAS  Google Scholar 

  16. Chang, G. & Roth, C.B. Structure of MsbA from E. coli: a homolog of the multidrug resistance ATP binding cassette (ABC) transporters. Science 293, 1793–1800 (2001).

    CAS  Google Scholar 

  17. Stenham, D.R. et al. An atomic detail model for the human ATP binding cassette transporter P-glycoprotein derived from disulfide cross-linking and homology modeling. FASEB J. 15, 2287–2289 (2003).

    Google Scholar 

  18. Senior, A.E., Al-Shawi, M.K. & Urbatsch, I.L. The catalytic cycle of P-glycoprotein. FEBS Lett. 377, 285–289 (1995).

    CAS  Google Scholar 

  19. Sauna, Z.E. & Ambudkar, S.V. Characterization of the catalytic cycle of ATP hydrolysis by human P-glycoprotein. The two ATP hydrolysis events in a single catalytic cycle are kinetically similar but affect different functional outcomes. J. Biol. Chem. 276, 11653–11661 (2001).

    CAS  Google Scholar 

  20. Nikaido, K. & Ames, G.F-L. One intact ATP-binding subunit is sufficient to support ATP hydrolysis and translocation in an ABC transporter, the histidine permease. J. Biol. Chem. 274, 26727–26735 (1999).

    CAS  Google Scholar 

  21. van Veen, H.W., Margolles, A., Müller, M., Higgins, C.F. & Konings, W.N. The homodimeric ATP-binding cassette transporter LmrA mediates multidrug transport by an alternating two-site (two-cylinder engine) mechanism. EMBO J. 19, 2503–2514 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lanket-Buttgereit, B. & Tampé, R. The transporter associated with antigen processing: function and implications in human diseases. Physiol. Rev. 82, 187–202 (2001).

    Google Scholar 

  23. Senior, A.E. & Gadsby, D.C. ATP hydrolysis cycles and mechanism in P-glycoprotein and CFTR. Sem. Cancer Biol. 8, 143–150 (1997).

    CAS  Google Scholar 

  24. Ames, G.F.-L. & Nikaido, K. Phosphate-containing proteins of Salmonella typhimurium and Escherichia coli. Analysis by a new two-dimensional gel system. Eur. J. Biochem. 115, 525–531 (1981).

    CAS  Google Scholar 

  25. Petronilli, V. & Ames, G.F.-L. Binding protein-independent histidine permease mutants. Uncoupling of ATP hydrolysis from transmembrane signaling. J. Biol. Chem. 266, 16293–16296 (1991).

    CAS  Google Scholar 

  26. Davidson, A.L., Shuman, H.A. & Nikaido, H. Mechanism of maltose transport in Escherichia coli: transmembrane signaling by periplasmic binding proteins. Proc. Natl. Acad. Sci USA. 89, 2360–2364 (1992).

    CAS  PubMed  Google Scholar 

  27. Liu, R. & Sharom, F.J. Site-directed fluorescence labelling of P-glycoprotein on cysteine residues in the nucleotide binding domains. Biochemistry 35, 11865–11873 (1996).

    CAS  Google Scholar 

  28. Sonveaux, N., Vigano, C., Shapiro, A.B., Ling, V. & Ruysschaert, J.-M. Ligand-mediated tertiary structure changes of reconstituted P-glycoprotein. A tryptophan fluorescence quenching analysis. J. Biol. Chem. 274, 17649–17654 (1999).

    CAS  Google Scholar 

  29. Neumann, L., Abele, R. & Tampé, R. Thermodynamics of peptide binding to the transporter associated with antigen processing (TAP). J. Mol. Biol. 324, 965–973 (2002).

    CAS  Google Scholar 

  30. Manciu, L. et al. Intermediate structural states involved in MRP1-mediated drug transport. Role of glutathione. J. Biol. Chem. 278, 3347–3356 (2003).

    CAS  Google Scholar 

  31. Kreimer, D.I., Chai, K.P. & Ames, G.F.-L. Nonequivalence of the nucleotide-binding subunits of an ABC transporter, the histidine permease, and conformational changes in the membrane complex. Biochemistry 39, 14183–14195 (2000).

    CAS  Google Scholar 

  32. Mannering, D.E., Sharma, S. & Davidson, A.L. Demonstration of conformational changes associated with activation of the maltose transport complex. J. Biol. Chem. 376, 12362–12368 (2001).

    Google Scholar 

  33. Sarkadi, B., Price, E.M., Boucher, R.C., Germann, U.A. & Scarborough, G.A. Expression of the human multidrug resistance cDNA in insect cells generates a high activity drug-stimulated membrane ATPase. J. Biol. Chem. 267, 4854–4858 (1992).

    CAS  Google Scholar 

  34. Gradia, S., Acharya, S. & Fishel, R. The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch. Cell 91, 995–1005 (1997).

    CAS  Google Scholar 

  35. Nikaido, K., Liu, P.-Q. & Ames, G.F.-L. Purification and characterization of HisP, the ATP-binding subunit of a traffic ATPase (ABC transporter), the histidine permease of Salmonella typhimurium. Solubility, dimerization, and ATPase activity. J. Biol. Chem. 272, 27745–27752 (1997).

    CAS  Google Scholar 

  36. Gao, M. et al. Comparison of the functional characteristics of the nucleotide binding domains of multidrug resistance protein 1. J. Biol. Chem. 275, 13098–13108 (2000).

    CAS  Google Scholar 

  37. Qu, Q., Russell, P.L. & Sharom, F.J. Stoichiometry and affinity of nucleotide binding to P-glycoprotein during the catalytic cycle. Biochemistry 42, 1170–1177 (2003).

    CAS  Google Scholar 

  38. Gradia, S. et al. hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. Mol. Cell 3, 255–261 (1999).

    CAS  Google Scholar 

  39. Lamers, M.H., Winterwerp, H.H.K. & Sixma, T.K. The alternating ATPase domains of MutS control DNA mismatch repair. EMBO J. 22, 746–756 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Mourez, M., Hofnung, M. & Dassa, E. Subunit interactions in ABC transporters: a conserved sequence in hydrophobic membrane proteins of periplasmic permeases defines an important site of interaction with the ATPase subunits. EMBO J. 16, 3066–3077 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Schmitt, L., Benabdelhak, H., Blight, M.A., Holland, I.B. & Stubbs, M.A. Crystal structure of the nucleotide-binding domain of the ABC-transporter haemolysin B: identification of a variable region within ABC helical domains. J. Mol. Biol. 330, 333–342 (2003).

    CAS  Google Scholar 

  42. Verdon, G., Albers, S.V., Dijkstra, B.W., Driessen, A.J.M. & Thunnissen, A.-M. Formation of the productive ATP-Mg2+-bound dimer of GlcV, an ABC-ATPase from Sulfolobus solfataricus. J. Mol. Biol. 330, 343–358 (2003).

    CAS  Google Scholar 

  43. Mitchell, P. A general theory of membrane transport from studies of bacteria. Nature 180, 134–136 (1957).

    CAS  Google Scholar 

  44. Martin, C. et al. Communication between multiple drug binding sites on P-glycoprotein. Mol. Pharmacol. 58, 624–632 (2000).

    CAS  Google Scholar 

  45. Martin, C., Higgins, C.F. & Callaghan, R. The vinblastine binding site adopts high- and low-affinity conformations during a transport cycle of P-glycoprotein. Biochemistry 40, 15733–15742 (2001).

    CAS  Google Scholar 

  46. Payen, L.F., Gao, M., Westlake, C.J., Cole, S.P.C. & Deeley, R.G. Role of carboxylate residues adjacent to the conserved core Walker B motifs in the catalytic cycle of multidrug resistance protein 1 (ABCC1). J. Biol. Chem. 278, 38537–38547 (2003).

    CAS  Google Scholar 

  47. Aleksandrov, A.A., Chang, X.-B., Aleksandrov, L. & Riordan, J. The non-hydrolytic pathway of cystic fibrosis transmembrane conductance regulator ion channel gating. J. Physiol. 528, 259–265 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Vergani, P., Nairn, A.C. & Gadsby, D.C. On the mechanism of MgATP-dependent gating of CFTR Cl− channels. J. Gen. Physiol. 120, 17–36 (2003).

    Google Scholar 

  49. Vigano, C., Margolles, A., van Veen, H.W., Konings, W.N. & Ruyssschaert, J.-M. Secondary and tertiary structure changes of reconstituted LmrA induced by nucleotide binding or hydrolysis. A fourier transform attenuated total reflection infrared spectroscopy and tryptophan fluorescence quenching analysis. J. Biol. Chem. 275, 10962–10967 (2000).

    CAS  Google Scholar 

  50. Linton, K.J. & Higgins, C.F. P-glycoprotein misfolds in Escherichia coli: evidence against alternating-topology models of the transport cycle. Mol. Membr. Biol. 19, 51–58 (2002).

    CAS  Google Scholar 

  51. Chen, J., Lu, G., Lin, J., Davidson, A.L. & Quiocho, F.A. A tweezers-like motion of the ATP-binding cassette dimer in an ABC transport cycle. Mol. Cell 12, 651–661 (2003).

    CAS  Google Scholar 

  52. Liu, R. & Sharom, F.J. FRET analysis indicates that the two ATPase active sites of the P-glycoprotein multidrug transporter are closely associated. Biochemistry 36, 2836–2843 (1997).

    CAS  Google Scholar 

  53. Loo, T.W. & Clarke, D.M. Identification of residues within the drug-binding domain of the human multidrug resistance P-glycoprotein by cysteine-scanning mutagenesis and reaction with dibromobimane. J. Biol. Chem. 275, 39272–39278 (2000).

    CAS  Google Scholar 

  54. Liu, C.E., Liu, P.-Q. & Ames, G.F.-L. Characterization of the adenosine triphosphatase activity of the periplasmic histidine permease, a traffic ATPase (ABC transporter). J. Biol. Chem. 272, 21883–21891 (1997).

    CAS  Google Scholar 

  55. Davidson, A.L. & Sharma, S. Mutation of a single MalK subunit severely impairs maltose transport activity in Escherichia coli. J. Bacteriol. 179, 5458–5464 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hou, Y-X, Riordan, J.R. & Chang, X-B. ATP binding, not hydrolysis, at the first nucleotide-binding domain of multidrug resistance-associated protein MRP1 enhances ADP.Vi trapping at the second domain. J. Biol. Chem. 278, 3599–3605 (2003).

    CAS  Google Scholar 

  57. Hrycyna, C.A. et al. Mechanism of action of human P-glycoprotein ATPase activity. Photochemical cleavage during a catalytic transition state using orthovanadate reveals cross-talk between the two ATP sites. J. Biol. Chem. 273, 16631–16634 (1998).

    CAS  Google Scholar 

  58. Hrycyna, C.A. et al. Both ATP sites of human P-glycoprotein are essential but not symmetric. Biochemistry 38, 13887–13899 (1999).

    CAS  Google Scholar 

  59. Urbatsch, I.L., Sankaran, B., Weber, J. & Senior, A.E. Both P-glycoprotein nucleotide-binding sites are catalytically active. J. Biol. Chem. 270, 19383–19390 (1995).

    CAS  Google Scholar 

  60. Urbatsch, I.L., Tyndall, G.A., Tombline, G. & Senior, A.E. P-glycoprotein catalytic mechanism: studies of the ADP-vanadate inhibited state. J. Biol. Chem. 278, 23171–23179 (2003).

    CAS  Google Scholar 

  61. Ramachandra, M. et al. Human P-glycoprotein exhibits reduced affinity for substrates during a catalytic transition state. Biochemistry 37, 5010–5019 (1998).

    CAS  Google Scholar 

  62. Chen, J.S., Sharma, S., Quiocho, F.A. & Davidson, A.L. Trapping the transition state of an ATP-binding cassette transporter: evidence for a concerted mechanism of maltose transport. Proc. Natl. Acad. Sci USA. 98, 1525–1530 (2001)

    CAS  PubMed  Google Scholar 

  63. Qu, Q., Chu, W.K. & Sharom, F.J. Transition state P-glycoprotein binds drugs and modulators with unchanged affinity, suggesting a concerted transport mechanism. Biochemistry 42, 1345–1353 (2003).

    CAS  Google Scholar 

  64. Sharma, S. & Davidson, A.L. Vanadate-induced trapping of nucleotides by purified maltose transport complex requires ATP hydrolysis. J. Bacteriol. 182, 6570–6576 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Janas, E. et al. The ATP hydrolysis cycle of the nucleotide-binding domain of the mitochondrial ATP-binding cassette transporter Mdl1p. J. Biol. Chem. 278, 26862–26869 (2003).

    CAS  Google Scholar 

  66. Kerr, K.M., Sauna, Z.E. & Ambudkar, S.V. Correlation between steady-state ATP hydrolysis and vanadate-induced ADP trapping in Human P-glycoprotein. Evidence for ADP release as the rate-limiting step in the catalytic cycle and its modulation by substrates. J. Biol. Chem. 276, 8657–8664 (2001).

    CAS  Google Scholar 

  67. Sauna, Z.E. & Ambudkar, S.V. Evidence for a requirement for ATP hydrolysis at two distinct steps during a single turnover of the catalytic cycle of human P-glycoprotein. Proc. Natl. Acad. Sci. USA 97, 2515–2520 (2000).

    CAS  PubMed  Google Scholar 

  68. Al-Shawi, M.K., Polar, M.K., Omote, H. & Figler, R.A. Transition state analysis of the coupling of drug transport to ATP hydrolysis by P-glycoprotein. J. Biol. Chem. 278, 56269–52640 (2003).

    Google Scholar 

  69. Omote, H. & Al-Shawi, M.K. A novel electron paramagnetic resonance approach to determine the mechanism of drug transport by P-glycoprotein. J. Biol. Chem. 277, 45688–45694 (2002).

    CAS  Google Scholar 

  70. Venter, H., Shilling, R.A., Velamakanni, S., Balakrishnan, L. & van Veen, H.W. An ABC transporter with a secondary-active multidrug translocator domain. Nature 426, 866–870 (2003).

    CAS  Google Scholar 

  71. Balakrishnan, L., Venter, H., Shilling, R.A. & van Veen H. Reversible transport by the ATP-binding cassette multidrug export pump LmrA: ATP synthesis at the expense of downhill ethidium uptake. J. Biol. Chem. 279, 11273–11280 (2004).

    CAS  Google Scholar 

  72. Urbatsch, I.L., Beaudet, L., Carrier, I. & Gros, P. Mutations in either nucleotide-binding site of P-glycoprotein (Mdr3) prevent vanadate trapping of nucleotide at both sites. Biochemistry 37, 4592–4602 (1998).

    CAS  Google Scholar 

  73. Szabó, K. et al. Drug-stimulated nucleotide trapping in the human multidrug transporter MDR1. Cooperation of the nucleotide binding domains. J. Biol. Chem. 273, 10132–10138 (1998).

    Google Scholar 

  74. Chen, M., Abele, R. & Tampé R. Peptides induce ATP hydrolysis at both subunits of the transporter associated with antigen processing. J. Biol. Chem. 278, 29686–29692 (2003).

    CAS  Google Scholar 

  75. Tombline, G., Bartholomew, L., Gimi, K., Gyndall, G.A. & Senior, A.E. Combined mutation of catalytic glutamate residues in the two nucleotide binding domains of P-glycoprotein generates a conformation that binds ATP and ADP tightly. J. Biol. Chem. 279, 31212–31220 (2003).

    Google Scholar 

  76. Basso, C., Vergani, P., Nairn, A.C., Gadsby, D.C. Prolonged nonhydrolytic interaction of nucleotide with CFTR's NH2-terminal nucleotide binding domain and its role in channel gating. J. Gen. Physiol. 122, 333–348 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Davidson, A.L., Laghaeian, S.S. & Mannering, D.E. The maltose transport system of Escherichia coli displays positive cooperativity in ATP hydrolysis. J. Biol. Chem. 271, 4858–4863 (1996).

    CAS  Google Scholar 

  78. Carrier, I., Julien, M. & Gros, P. Analysis of catalytic carboxylate mutants E552Q and E1197Q suggests asymmetric ATP hydrolysis by the two nucleotide-binding domains of P-glycoprotein. Biochemistry 42, 12875–12885 (2003).

    CAS  Google Scholar 

  79. Loo, T.W. & Clarke, D.M. Covalent modification of human P-glycoprotein mutants containing a single cysteine in either nucleotide-binding fold abolishes drug-stimulated ATPase activity. J. Biol. Chem. 270, 22957–22961 (1995).

    CAS  Google Scholar 

  80. Yang, R., Cui, L., Hou, Y.-X., Riordan, J.R. & Chang, X.-B. ATP binding to the first nucleotide binding domain of multidrug resistance-associated protein plays a regulatory role at low nucleotide concentration, whereas ATP hydrolysis at the second plays a dominant role in ATP-dependent leukotriene C4 transport. J. Biol. Chem. 33, 30764–30771 (2003).

    Google Scholar 

  81. Ueda, K., Komine, J., Matsuo, M., Seino, S. & Amachi, T. Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. Proc. Natl. Acad. Sci USA. 96, 1268–1272 (1999).

    CAS  PubMed  Google Scholar 

  82. Nagata, K. et al. Nonequivalent nucleotide trapping in the two nucleotide binding folds of the human multidrug resistance protein MRP1. J. Biol. Chem. 275, 17626–17630 (2000).

    CAS  Google Scholar 

  83. Guderson, K.L. & Kopito, R.R. Conformational states of CFTR associated with channel gating: the role ATP binding and hydrolysis. Cell 82, 231–239 (1995).

    Google Scholar 

  84. Carson, M.R., Travis, S.M. & Welsh, M.J. The two nucleotide-binding domains of cystic fibrosis transmembrane conductance regulator (CFTR) have distinct functions in controlling channel activity. J. Biol. Chem. 270, 1711–1717 (1995).

    CAS  Google Scholar 

  85. Uebel, S. et al. Requirements for peptide binding to the human transporter associated with antigen processing revealed by peptide scans and complex peptide libraries. J. Biol. Chem. 270, 18512–18516 (1995).

    CAS  Google Scholar 

  86. Loe, D.W., Deeley, R.G. & Cole, S.P.C. Characterization of vincristine transport by the M(r) 190,000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione. Cancer Res. 58, 5130–5136 (1998).

    CAS  Google Scholar 

  87. Rius, M., Nies, A.J., Hummel-Eisenbeiss, J., Jedlitschky, G. & Keppler, D. Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology 38, 374–384 (2003).

    CAS  Google Scholar 

  88. Martin, C., Berridge, G., Higgins, C.F., Callaghan, R. The multi-drug resistance reversal agent SR33557 and modulation of vinca alkaloid binding to P-glycoprotein by an allosteric interaction. Br. J. Pharmacol. 122, 765–771 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Martin, C. et al. Drug binding sites on P-glycoprotein are altered by ATP binding prior to nucleotide hydrolysis. Biochemistry 39, 11901–11906 (2000).

    CAS  Google Scholar 

  90. Zelcer, N. et al. Evidence for two interacting ligand binding sites in human multidrug resistance protein 2 (ATP binding cassette C2). J. Biol. Chem. 278, 23538–23544 (2003).

    CAS  Google Scholar 

  91. Shapiro, A.B. & Ling, V. Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur. J. Biochem. 250, 130–137 (1997).

    CAS  Google Scholar 

  92. Shapiro, A.B. & Ling, V. Stoichiometry of coupling of rhodamine 123 transport to ATP hydrolysis by P-glycoprotein. Eur. J. Biochem. 254, 189–193 (1998).

    CAS  Google Scholar 

  93. Ambudkar, S.V., Cardarelli, C.O., Pashinsky, I., Stein, W.D. Relation between the turnover number for vinblastine transport and for vinblastine-stimulated ATP hydrolysis by human P-glycoprotein. J. Biol. Chem. 272, 21160–21166 (1997).

    CAS  Google Scholar 

  94. Mao, B., Pear, M.R., McCammon, J.A. & Quiocho, F.A. Hinge-bending in L-arabinose-binding protein. The “Venus's-flytrap” model. J. Biol. Chem. 257, 1131–1133 (1982).

    CAS  Google Scholar 

  95. Sharff, A.J., Rodeseth, L.E., Spurling, J.E. & Quiocho, F.A. Crystallographic evidence of a large ligand-induced hinge-twist motion between the two domains of the maltodextrin binding protein involved in active transport and chemotaxis. Biochemistry 31, 10657–10663 (1992).

    CAS  Google Scholar 

  96. Binnie, R.A., Zhang, H., Mowbray, S. & Hermodson, M.A. Functional mapping of the surface of Escherichia coli ribose-binding protein: mutations that affect chemotaxis and transport. Protein Sci. 1, 1642–1651 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Borths, E.L., Locher, K.P., Lee, A.T. & Rees, D.C. The structure of Escherichia coli BtuF and binding to its cognate ATP binding cassette transporter. Proc. Natl. Acad. Sci. USA 99, 16642–16647 (2002).

    CAS  PubMed  Google Scholar 

  98. Shuman, H.A. Active transport of maltose in Escherichia coli K12. Role of the periplasmic maltose-binding protein and evidence for a substrate recognition site in the cytoplasmic membrane. J. Biol. Chem. 257, 5455–5461 (1982).

    CAS  Google Scholar 

  99. Speiser, D.M. & Ames, G.F.-L. Salmonella typhimurium histidine periplasmic permease mutations that allow transport in the absence of histidine-binding proteins. J. Bacteriol. 173, 1444–1451 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful for the contributions of many present and former members of the laboratory and collaborators, particularly R. Callaghan, R. van Veen, C. Martin, R.Ford and M. Rosenberg. We also thank many colleagues throughout the world for sharing information and stimulating discussions. The authors' research is funded by the UK Medical Research Council.

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  1. MRC Clinical Sciences Centre, Imperial College Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK

    Christopher F Higgins & Kenneth J Linton

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Correspondence to Christopher F Higgins.

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Higgins, C., Linton, K. The ATP switch model for ABC transporters. Nat Struct Mol Biol 11, 918–926 (2004). https://doi.org/10.1038/nsmb836

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