Cysteine accessibility probes timing and extent of NBD separation along the dimer interface in gating CFTR channels

Journal of General Physiology

Volumn 145, Issue 4, 2015, Pages 261-283

  Chaves, Luiz A Poletto ^a   Gadsby, David C ^a  

^a ROCKEFELLER UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; CFTR PROTEIN, HUMAN; CYSTEINE; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; PROTEIN BINDING; PROTEIN SUBUNIT;

AMINO ACID SEQUENCE; AMINO ACID SUBSTITUTION; ANIMAL; CHANNEL GATING; CHEMISTRY; GENETICS; HUMAN; METABOLISM; MOLECULAR GENETICS; PROTEIN MOTIF; PROTEIN SUBUNIT; PROTEIN TERTIARY STRUCTURE; XENOPUS;

ADENOSINE TRIPHOSPHATE; AMINO ACID MOTIFS; AMINO ACID SEQUENCE; AMINO ACID SUBSTITUTION; ANIMALS; CYSTEINE; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; HUMANS; ION CHANNEL GATING; MOLECULAR SEQUENCE DATA; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; PROTEIN SUBUNITS; XENOPUS;

EID: 84928229130     PISSN: 00221295     EISSN: 15407748     Source Type: Journal    
DOI: 10.1085/jgp.201411347     Document Type: Article

References (78)

1. Aleksandrov, L., A.A. Aleksandrov, X.B. Chang, and J.R. Riordan. 2002. The first nucleotide binding domain of cystic fibrosis transmembrane conductance regulator is a site of stable nucleotide interaction, whereas the second is a site of rapid turnover. J. Biol. Chem. 277:15419-15425. http://dx.doi.org/10.1074/jbc.M111713200
2. Aleksandrov, L., A. Aleksandrov, and J.R. Riordan. 2008. Mg2+-dependent ATP occlusion at the first nucleotide-binding domain (NBD1) of CFTR does not require the second (NBD2). Biochem. J. 416:129-136. http://dx.doi.org/10.1042/BJ20081068
3. Aller, S.G., J. Yu, A. Ward, Y. Weng, S. Chittaboina, R. Zhuo, P.M. Harrell, Y.T. Trinh, Q. Zhang, I.L. Urbatsch, and G. Chang. 2009. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 323:1718-1722. http://dx.doi.org/10.1126/science.1168750
4. Bai, Y., M. Li, and T.C. Hwang. 2010. Dual roles of the sixth transmembrane segment of the CFTR chloride channel in gating and permeation. J. Gen. Physiol. 136:293-309. http://dx.doi.org/10.1085/jgp.201010480
5. Basso, C., P. Vergani, A.C. Nairn, and D.C. Gadsby. 2003. 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. http://dx.doi.org/10.1085/jgp.200308798
6. Baukrowitz, T., T.C. Hwang, A.C. Nairn, and D.C. Gadsby. 1994. Coupling of CFTR Cl- channel gating to an ATP hydrolysis cycle. Neuron. 12:473-482. http://dx.doi.org/10.1016/0896-6273(94)90206-2
7. Boël, G., P.C. Smith, W. Ning, M.T. Englander, B. Chen, Y. Hashem, A.J. Testa, J.J. Fischer, H.J. Wieden, J. Frank, et al. 2014. The ABC-F protein EttA gates ribosome entry into the translation elongation cycle. Nat. Struct. Mol. Biol. 21:143-151. http://dx.doi .org/10.1038/nsmb.2740
8. Cai, Z., T.S. Scott-Ward, and D.N. Sheppard. 2003. Voltage-dependent gating of the cystic fibrosis transmembrane conductance regulator Cl- channel. J. Gen. Physiol. 122:605-620. http://dx.doi.org/10.1085/jgp.200308921
9. Carson, M.R., S.M. Travis, and M.J. Welsh. 1995. The two nucleotidebinding domains of cystic fibrosis transmembrane conductance regulator (CFTR) have distinct functions in controlling channel activity. J. Biol. Chem. 270:1711-1717. http://dx.doi.org/10.1074/jbc.270.4.1711
10. Chan, K.W., L. Csanády, D. Seto-Young, A.C. Nairn, and D.C. Gadsby. 2000. Severed molecules functionally define the boundaries of the cystic fibrosis transmembrane conductance regulator's Nh2-terminal nucleotide binding domain. J. Gen. Physiol. 116:163-180. http://dx.doi.org/10.1085/jgp.116.2.163
11. Chen, T.Y., and T.C. Hwang. 2008. CLC-0 and CFTR: Chloride channels evolved from transporters. Physiol. Rev. 88:351-387. http://dx.doi.org/10.1152/physrev.00058.2006
12. Chen, J., G. Lu, J. Lin, A.L. Davidson, and F.A. Quiocho. 2003. A tweezers-like motion of the ATP-binding cassette dimer in an ABC transport cycle. Mol. Cell. 12:651-661. http://dx.doi.org/10.1016/j.molcel.2003.08.004
13. Cotten, J.F., and M.J. Welsh. 1997. Covalent modification of the regulatory domain irreversibly stimulates cystic fibrosis transmembrane conductance regulator. J. Biol. Chem. 272:25617-25622.http://dx.doi.org/10.1074/jbc.272.41.25617
14. Cotten, J.F., and M.J. Welsh. 1998. Covalent modification of the nucleotide binding domains of cystic fibrosis transmembrane conductance regulator. J. Biol. Chem. 273:31873-31879. http://dx .doi.org/10.1074/jbc.273.48.31873
15. Csanády, L., K.W. Chan, D. Seto-Young, D.C. Kopsco, A.C. Nairn, and D.C. Gadsby. 2000. Severed channels probe regulation of gating of cystic fibrosis transmembrane conductance regulator by its cytoplasmic domains. J. Gen. Physiol. 116:477-500. http://dx.doi .org/10.1085/jgp.116.3.477
16. Csanády, L., A.C. Nairn, and D.C. Gadsby. 2006. Thermodynamics of CFTR channel gating: A spreading conformational change initiates an irreversible gating cycle. J. Gen. Physiol. 128:523-533.http://dx.doi.org/10.1085/jgp.200609558
17. Csanády, L., P. Vergani, and D.C. Gadsby. 2010. Strict coupling between CFTR's catalytic cycle and gating of its Cl- ion pore revealed by distributions of open channel burst durations. Proc. Natl. Acad. Sci. USA. 107:1241-1246. http://dx.doi.org/10.1073/pnas.0911061107
18. Csanády, L., C. Mihályi, A. Szollosi, B. Töröcsik, and P. Vergani. 2013. Conformational changes in the catalytically inactive nucleotide-binding site of CFTR. J. Gen. Physiol. 142:61-73. http://dx.doi.org/10.1085/jgp.201210954
19. Cui, L., L. Aleksandrov, Y.X. Hou, M. Gentzsch, J.H. Chen, J.R. Riordan, and A.A. Aleksandrov. 2006. The role of cystic fibrosis transmembrane conductance regulator phenylalanine 508 side chain in ion channel gating. J. Physiol. 572:347-358. http://dx.doi .org/10.1113/jphysiol.2005.099457
20. Davidson, A.L., E. Dassa, C. Orelle, and J. Chen. 2008. Structure, function, and evolution of bacterial ATP-binding cassette systems. Microbiol. Mol. Biol. Rev. 72:317-364. http://dx.doi.org/10.1128/MMBR.00031-07
21. Dawson, R.J., and K.P. Locher. 2006. Structure of a bacterial multidrug ABC transporter. Nature. 443:180-185. http://dx.doi.org/10.1038/nature05155
22. Dawson, R.J., and K.P. Locher. 2007. Structure of the multidrug ABC transporter Sav1866 from Staphylococcus aureus in complex with AMP-PNP. FEBS Lett. 581:935-938. http://dx.doi.org/10.1016/j.febslet.2007.01.073
23. Fetsch, E.E., and A.L. Davidson. 2002. Vanadate-catalyzed photocleavage of the signature motif of an ATP-binding cassette (ABC) transporter. Proc. Natl. Acad. Sci. USA. 99:9685-9690. http://dx .doi.org/10.1073/pnas.152204499
24. Gadsby, D.C., P. Vergani, and L. Csanády. 2006. The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature. 440:477-483. http://dx.doi.org/10.1038/nature04712
25. Gao, M., H.R. Cui, D.W. Loe, C.E. Grant, K.C. Almquist, S.P. Cole, and R.G. Deeley. 2000. Comparison of the functional characteristics of the nucleotide binding domains of multidrug resistance protein 1. J. Biol. Chem. 275:13098-13108. http://dx.doi.org/10.1074/jbc.275.17.13098
26. Gunderson, K.L., and R.R. Kopito. 1994. Effects of pyrophosphate and nucleotide analogs suggest a role for ATP hydrolysis in cystic fibrosis transmembrane regulator channel gating. J. Biol. Chem.269:19349-19353.
27. Gunderson, K.L., and R.R. Kopito. 1995. Conformational states of CFTR associated with channel gating: The role ATP binding and hydrolysis. Cell. 82:231-239. http://dx.doi.org/10.1016/0092-8674(95)90310-0
28. Hohl, M., C. Briand, M.G. Grütter, and M.A. Seeger. 2012. Crystal structure of a heterodimeric ABC transporter in its inward-facing conformation. Nat. Struct. Mol. Biol. 19:395-402. http://dx.doi .org/10.1038/nsmb.2267
29. Hohl, M., L.M. Hürlimann, S. Böhm, J. Schöppe, M.G. Grütter, E. Bordignon, and M.A. Seeger. 2014. Structural basis for allosteric cross-talk between the asymmetric nucleotide binding sites of a heterodimeric ABC exporter. Proc. Natl. Acad. Sci. USA. 111:11025-11030. http://dx.doi.org/10.1073/pnas.1400485111
30. Hopfner, K.P., and J.A. Tainer. 2003. Rad50/SMC proteins and ABC transporters: unifying concepts from high-resolution structures. Curr. Opin. Struct. Biol. 13:249-255. http://dx.doi.org/10.1016/S0959-440X(03)00037-X
31. Hopfner, K.P., A. Karcher, D.S. Shin, L. Craig, L.M. Arthur, J.P. Carney, and J.A. Tainer. 2000. Structural biology of Rad50 ATPase: ATPdriven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell. 101:789-800. http://dx .doi.org/10.1016/S0092-8674(00)80890-9
32. Hou, Y., L. Cui, J.R. Riordan, and X. Chang. 2000. Allosteric interactions between the two non-equivalent nucleotide binding domains of multidrug resistance protein MRP1. J. Biol. Chem. 275:20280-20287. http://dx.doi.org/10.1074/jbc.M001109200
33. Hung, L.W., I.X. Wang, K. Nikaido, P.Q. Liu, G.F. Ames, and S.H. Kim. 1998. Crystal structure of the ATP-binding subunit of an ABC transporter. Nature. 396:703-707. http://dx.doi.org/10.1038/25393
34. Janas, E., M. Hofacker, M. Chen, S. Gompf, C. van der Does, and R. Tampé. 2003. The ATP hydrolysis cycle of the nucleotide-binding domain of the mitochondrial ATP-binding cassette transporter Mdl1p. J. Biol. Chem. 278:26862-26869. http://dx.doi.org/10.1074/jbc.M301227200
35. Jin, M.S., M.L. Oldham, Q. Zhang, and J. Chen. 2012. Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. Nature. 490:566-569. http://dx.doi.org/10.1038/nature11448
36. Karlin, A., and M.H. Akabas. 1998. Substituted-cysteine accessibility method. Methods Enzymol. 293:123-145. http://dx.doi.org/10.1016/S0076-6879(98)93011-7
37. Khare, D., M.L. Oldham, C. Orelle, A.L. Davidson, and J. Chen. 2009. Alternating access in maltose transporter mediated by rigid-body rotations. Mol. Cell. 33:528-536. http://dx.doi.org/10.1016/j .molcel.2009.01.035
38. Kim, J., S. Wu, T.M. Tomasiak, C. Mergel, M.B. Winter, S.B. Stiller, Y. Robles-Colmanares, R.M. Stroud, R. Tampé, C.S. Craik, and Y. Cheng. 2015. Subnanometre-resolution electron cryomicroscopy structure of a heterodimeric ABC exporter. Nature. 517:396-400. http://dx.doi.org/10.1038/nature13872
39. Kodan, A., T. Yamaguchi, T. Nakatsu, K. Sakiyama, C.J. Hipolito, A. Fujioka, R. Hirokane, K. Ikeguchi, B. Watanabe, J. Hiratake, et al. 2014. Structural basis for gating mechanisms of a eukaryotic P-glycoprotein homolog. Proc. Natl. Acad. Sci. USA. 111:4049-4054. http://dx.doi.org/10.1073/pnas.1321562111
40. Kuruma, A., and H.C. Hartzell. 2000. Bimodal control of a Ca2+-activated Cl- channel by different Ca2+ signals. J. Gen. Physiol. 115:59-80. http://dx.doi.org/10.1085/jgp.115.1.59
41. Lamers, M.H., H.H. Winterwerp, and T.K. Sixma. 2003. The alternating ATPase domains of MutS control DNA mismatch repair. EMBO J. 22:746-756. http://dx.doi.org/10.1093/emboj/cdg064
42. Lee, J.Y., J.G. Yang, D. Zhitnitsky, O. Lewinson, and D.C. Rees. 2014. Structural basis for heavy metal detoxification by an Atm1-type ABC exporter. Science. 343:1133-1136. http://dx.doi.org/10.1126/science.1246489
43. Lerner-Marmarosh, N., K. Gimi, I.L. Urbatsch, P. Gros, and A.E. Senior. 1999. Large scale purification of detergent-soluble P-glycoprotein from Pichia pastoris cells and characterization of nucleotide binding properties of wild-type, Walker A, and Walker B mutant proteins. J. Biol. Chem. 274:34711-34718. http://dx.doi .org/10.1074/jbc.274.49.34711
44. Lewis, H.A., S.G. Buchanan, S.K. Burley, K. Conners, M. Dickey, M. Dorwart, R. Fowler, X. Gao, W.B. Guggino, W.A. Hendrickson, et al. 2004. Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO J. 23:282-293.
45. Li, C.H., Y.X. Yang, J.G. Su, B. Liu, J.J. Tan, X.Y. Zhang, and C.X. Wang. 2014. Allosteric transitions of the maltose transporter studied by an elastic network model. Biopolymers. 101:758-768. http://dx.doi.org/10.1002/bip.22455
46. Loo, T.W., and D.M. Clarke. 2000. Drug-stimulated ATPase activity of human P-glycoprotein is blocked by disulfide cross-linking between the nucleotide-binding sites. J. Biol. Chem. 275:19435-19438. http://dx.doi.org/10.1074/jbc.C000222200
47. Lubelski, J., A. de Jong, R. van Merkerk, H. Agustiandari, O.P. Kuipers, J. Kok, and A.J. Driessen. 2006. LmrCD is a major multidrug resistance transporter in Lactococcus lactis. Mol. Microbiol. 61:771-781. http://dx.doi.org/10.1111/j.1365-2958.2006.05267.x
48. Matsuo, M., N. Kioka, T. Amachi, and K. Ueda. 1999. ATP binding properties of the nucleotide-binding folds of SUR1. J. Biol. Chem. 274:37479-37482. http://dx.doi.org/10.1074/jbc.274.52.37479
49. Mense, M., P. Vergani, D.M. White, G. Altberg, A.C. Nairn, and D.C. Gadsby. 2006. In vivo phosphorylation of CFTR promotes formation of a nucleotide-binding domain heterodimer. EMBO J. 25:4728-4739. http://dx.doi.org/10.1038/sj.emboj.7601373
50. Moody, J.E., L. Millen, D. Binns, J.F. Hunt, and P.J. Thomas. 2002. Cooperative, ATP-dependent association of the nucleotide binding cassettes during the catalytic cycle of ATP-binding cassette transporters. J. Biol. Chem. 277:21111-21114. http://dx.doi.org/10.1074/jbc.C200228200
51. Moradi, M., and E. Tajkhorshid. 2013. Mechanistic picture for conformational transition of a membrane transporter at atomic resolution. Proc. Natl. Acad. Sci. USA. 110:18916-18921. http://dx.doi .org/10.1073/pnas.1313202110
52. Nagata, K., M. Nishitani, M. Matsuo, N. Kioka, T. Amachi, and K. Ueda. 2000. Nonequivalent nucleotide trapping in the two nucleotide binding folds of the human multidrug resistance protein MRP1. J. Biol. Chem. 275:17626-17630. http://dx.doi.org/10.1074/jbc.M000792200
53. Oldham, M.L., and J. Chen. 2011a. Crystal structure of the maltose transporter in a pretranslocation intermediate state. Science. 332:1202-1205. http://dx.doi.org/10.1126/science.1200767
54. Oldham, M.L., and J. Chen. 2011b. Snapshots of the maltose transporter during ATP hydrolysis. Proc. Natl. Acad. Sci. USA. 108:15152-15156. http://dx.doi.org/10.1073/pnas.1108858108
55. Powe, A.C., Jr., L. Al-Nakkash, M. Li, and T.C. Hwang. 2002. Mutation of Walker-A lysine 464 in cystic fibrosis transmembrane conductance regulator reveals functional interaction between its nucleotide-binding domains. J. Physiol. 539:333-346. http://dx .doi.org/10.1113/jphysiol.2001.013162
56. Procko, E., I. Ferrin-O'Connell, S.L. Ng, and R. Gaudet. 2006. Distinct structural and functional properties of the ATPase sites in an asymmetric ABC transporter. Mol. Cell. 24:51-62. http://dx.doi.org/10.1016/j.molcel.2006.07.034
57. Ramjeesingh, M., C. Li, E. Garami, L.J. Huan, K. Galley, Y. Wang, and C.E. Bear. 1999. Walker mutations reveal loose relationship between catalytic and channel-gating activities of purified CFTR (cystic fibrosis transmembrane conductance regulator). Biochemistry. 38:1463-1468. http://dx.doi.org/10.1021/bi982243y
58. Rees, D.C., E. Johnson, and O. Lewinson. 2009. ABC transporters: the power to change. Nat. Rev. Mol. Cell Biol. 10:218-227. http://dx.doi.org/10.1038/nrm2646
59. Senior, A.E., M.K. al-Shawi, and I.L. Urbatsch. 1995. The catalytic cycle of P-glycoprotein. FEBS Lett. 377:285-289. http://dx.doi .org/10.1016/0014-5793(95)01345-8
60. Shintre, C.A., A.C. Pike, Q. Li, J.I. Kim, A.J. Barr, S. Goubin, L. Shrestha, J. Yang, G. Berridge, J. Ross, et al. 2013. Structures of ABCB10, a human ATP-binding cassette transporter in apo- and nucleotide-bound states. Proc. Natl. Acad. Sci. USA. 110:9710-9715.
61. Siarheyeva, A., R. Liu, and F.J. Sharom. 2010. Characterization of an asymmetric occluded state of P-glycoprotein with two bound nucleotides: Implications for catalysis. J. Biol. Chem. 285:7575-7586. http://dx.doi.org/10.1074/jbc.M109.047290
62. Smith, P.C., N. Karpowich, L. Millen, J.E. Moody, J. Rosen, P.J. Thomas, and J.F. Hunt. 2002. ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer. Mol. Cell. 10:139-149. http://dx.doi.org/10.1016/S1097-2765(02)00576-2
63. Srinivasan, V., A.J. Pierik, and R. Lill. 2014. Crystal structures of nucleotide-free and glutathione-bound mitochondrial ABC transporter Atm1. Science. 343:1137-1140. http://dx.doi.org/10.1126/science.1246729
64. Szabó, K., G. Szakács, T. Hegeds, and B. Sarkadi. 1999. Nucleotide occlusion in the human cystic fibrosis transmembrane conductance regulator. Different patterns in the two nucleotide binding domains. J. Biol. Chem. 274:12209-12212. http://dx.doi.org/10.1074/jbc.274.18.12209
65. Szollosi, A., P. Vergani, and L. Csanády. 2010. Involvement of F1296 and N1303 of CFTR in induced-fit conformational change in response to ATP binding at NBD2. J. Gen. Physiol. 136:407-423.
66. Szollosi, A., D.R. Muallem, L. Csanády, and P. Vergani. 2011. Mutant cycles at CFTR's non-canonical ATP-binding site support little interface separation during gating. J. Gen. Physiol. 137:549-562. http://dx.doi.org/10.1085/jgp.201110608
67. Tombline, G., and A.E. Senior. 2005. The occluded nucleotide conformation of p-glycoprotein. J. Bioenerg. Biomembr. 37:497-500. http://dx.doi.org/10.1007/s10863-005-9498-4
68. Tsai, M.F., H. Shimizu, Y. Sohma, M. Li, and T.C. Hwang. 2009. State-dependent modulation of CFTR gating by pyrophosphate. J. Gen. Physiol. 133:405-419. http://dx.doi.org/10.1085/jgp .200810186
69. Tsai, M.F., M. Li, and T.C. Hwang. 2010. Stable ATP binding mediated by a partial NBD dimer of the CFTR chloride channel. J. Gen. Physiol. 135:399-414. http://dx.doi.org/10.1085/jgp.201010399
70. Urbatsch, I.L., B. Sankaran, S. Bhagat, and A.E. Senior. 1995. Both P-glycoprotein nucleotide-binding sites are catalytically active. J. Biol. Chem. 270:26956-26961. http://dx.doi.org/10.1074/jbc .270.45.26956
71. Urbatsch, I.L., K. Gimi, S. Wilke-Mounts, N. Lerner-Marmarosh, M.E. Rousseau, P. Gros, and A.E. Senior. 2001. Cysteines 431 and 1074 are responsible for inhibitory disulfide cross-linking between the two nucleotide-binding sites in human P-glycoprotein. J. Biol. Chem. 276:26980-26987. http://dx.doi.org/10.1074/jbc.M010829200
72. Verdon, G., S.V. Albers, N. van Oosterwijk, B.W. Dijkstra, A.J. Driessen, and A.M. Thunnissen. 2003. Formation of the productive ATP-Mg2+-bound dimer of GlcV, an ABC-ATPase from Sulfolobus solfataricus. J. Mol. Biol. 334:255-267. http://dx.doi.org/10.1016/j.jmb.2003.08.065
73. Vergani, P., A.C. Nairn, and D.C. Gadsby. 2003. On the mechanism of MgATP-dependent gating of CFTR Cl- channels. J. Gen. Physiol. 121:17-36. http://dx.doi.org/10.1085/jgp.20028673
74. Vergani, P., S.W. Lockless, A.C. Nairn, and D.C. Gadsby. 2005. CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains. Nature. 433:876-880. http://dx.doi .org/10.1038/nature03313
75. Ward, A., C.L. Reyes, J. Yu, C.B. Roth, and G. Chang. 2007. Flexibility in the ABC transporter MsbA: Alternating access with a twist. Proc. Natl. Acad. Sci. USA. 104:19005-19010. http://dx.doi.org/10.1073/pnas.0709388104
76. Ward, A.B., P. Szewczyk, V. Grimard, C.W. Lee, L. Martinez, R. Doshi, A. Caya, M. Villaluz, E. Pardon, C. Cregger, et al. 2013. Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain. Proc. Natl. Acad. Sci. USA.110:13386-13391. http://dx.doi.org/10.1073/pnas.1309275110
77. Zaitseva, J., S. Jenewein, A. Wiedenmann, H. Benabdelhak, I.B. Holland, and L. Schmitt. 2005. Functional characterization and ATP-induced dimerization of the isolated ABC-domain of the haemolysin B transporter. Biochemistry. 44:9680-9690.
78. Zutz, A., J. Hoffmann, U.A. Hellmich, C. Glaubitz, B. Ludwig, B. Brutschy, and R. Tampé. 2011. Asymmetric ATP hydrolysis cycle of the heterodimeric multidrug ABC transport complex TmrAB from Thermus thermophilus. J. Biol. Chem. 286:7104-7115. http://dx.doi.org/10.1074/jbc.M110.201178