Molecular modelling and molecular dynamics of CFTR

Cellular and Molecular Life Sciences

Volumn 74, Issue 1, 2017, Pages 3-22

  Callebaut, Isabelle ^a   Hoffmann, Brice ^a   Lehn, Pierre ^b   Mornon, Jean Paul ^a  

^a UNIVERSITÉ PIERRE ET MARIE CURIE   (France)

^b UNIVERSITÉ DE BRETAGNE OCCIDENTALE   (France)

Author keywords

ABC transporte; ABCC7; Cystic fibrosis; Ion channel; Modulators; Mutations

Indexed keywords

ABC TRANSPORTER; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; MEMBRANE PROTEIN; MULTIDRUG RESISTANCE PROTEIN; TRANSMEMBRANE PROTEIN 1; TRANSMEMBRANE PROTEIN 11; TRANSMEMBRANE PROTEIN 12; TRANSMEMBRANE PROTEIN 3; TRANSMEMBRANE PROTEIN 5; TRANSMEMBRANE PROTEIN 6; TRANSMEMBRANE PROTEIN 7; TRANSMEMBRANE PROTEIN 8; TRANSMEMBRANE PROTEIN 9; UNCLASSIFIED DRUG; LIGAND;

BINDING SITE; COMPUTER MODEL; CONFORMATIONAL TRANSITION; CYSTIC FIBROSIS; GENE MUTATION; HUMAN; MOLECULAR DYNAMICS; MOLECULAR IMAGING; MOLECULAR MODEL; NONHUMAN; PERSONALIZED MEDICINE; PROTEIN ASSEMBLY; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN MOTIF; PROTEIN STRUCTURE; REGULATORY MECHANISM; REVIEW; SEQUENCE ALIGNMENT; ANIMAL; CHEMISTRY; DRUG DESIGN; DRUG EFFECTS; GENETICS; METABOLISM; MOLECULAR DOCKING; MUTATION; PROTEIN CONFORMATION;

ANIMALS; CYSTIC FIBROSIS; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; DRUG DESIGN; HUMANS; LIGANDS; MOLECULAR DOCKING SIMULATION; MOLECULAR DYNAMICS SIMULATION; MUTATION; PROTEIN CONFORMATION;

EID: 84990950108     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-016-2385-9     Document Type: Review

References (200)

1. Dean M, Rzhetsky A, Allikmets R (2001) The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 11:1156–1566
2. ter Beek J, Guskov A, Slotboom DJ (2014) Structural diversity of ABC transporters. J Gen Physiol 143:419–435
3. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z et al (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073
4. Locher KP (2016) Mechanistic diversity in ATP-binding cassette (ABC) transporters. Nat Struct Mol Biol 23:487–493
5. Linsdell P (2006) Mechanism of chloride permeation in the cystic fibrosis transmembrane conductance regulator chloride channel. Exp Physiol 91:123–129
6. McCarty NA (2000) Permeation through the CFTR chloride channel. J Exp Biol 203:1947–1962
7. Muallem D, Vergani P (2009) ATP hydrolysis-driven gating in cystic fibrosis transmembrane conductance regulator. Philos Trans R Soc Lond B Biol Sci 364:247–255
8. Hwang TC, Sheppard DN (2009) Gating of the CFTR Cl-channel by ATP-driven nucleotide-binding domain dimerisation. J Physiol 587:2151–2161
9. Winter MC, Welsh MJ (1997) Stimulation of CFTR activity by its phosphorylated R domain. Nature 389:294–296
10. Liang X, Da Paula AC, Bozóky Z, Zhang H, Bertrand CA, Peters KW et al (2012) Phosphorylation-dependent 14-3-3 protein interactions regulate CFTR biogenesis. Mol Biol Cell 23:996–1009
11. Bozoky Z, Krzeminski M, Chong P, Forman-Kay JD (2013) Structural changes of CFTR R region upon phosphorylation: a plastic platform for intramolecular and intermolecular interactions. FEBS J 280:4407–4416
12. Chappe V, Irvine T, Liao J, Evagelidis A, Hanrahan JW (2005) Phosphorylation of CFTR by PKA promotes binding of the regulatory domain. EMBO J 24:2730–2740
13. Rowe SM, Miller S, Sorscher EJ (2005) Cystic fibrosis. N Engl J Med 352:1992–2001
14. Wang Y, Wrennall JA, Cai Z, Li H, Sheppard DN (2014) Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models. Int J Biochem Cell Biol 52:47–57
15. Veit G, Avramescu RG, Chiang AN, Houck SA, Cai Z, Peters KW et al (2016) From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell 27:424–433
16. Cutting GR (2015) Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet 16:45–56
17. Hunt JF, Wang C, Ford RC (2013) Cystic fibrosis transmembrane conductance regulator (ABCC7) structure. Cold Spring Harb Perspect Med 3:a009514
18. Bozoky Z, Krzeminski M, Muhandiram R, Birtley JR, Al-Zahrani A, Thomas PJ et al (2013) Regulatory R region of the CFTR chloride channel is a dynamic integrator of phospho-dependent intra- and intermolecular interactions. Proc Natl Acad Sci USA 110:E4427–E4436
19. Zhang L, Aleksandrov LA, Riordan JR, Ford RC (2011) Domain location within the cystic fibrosis transmembrane conductance regulator protein investigated by electron microscopy and gold labelling. Biochim Biophys Acta 1808:399–404
20. Zhang L, Aleksandrov LA, Z Z, Birtley JR, Riordan JR, Ford RC (2009) Architecture of the cystic fibrosis transmembrane conductance regulator protein and structural changes associated with phosphorylation and nucleotide binding. J Struct Biol 167:242–251
21. Rosenberg MF, O’Ryan LP, Hughes G, Zhao Z, Aleksandrov LA, Riordan JR et al (2011) The cystic fibrosis transmembrane conductance regulator (CFTR): three-dimensional structure and localization of a channel gate. J Biol Chem 286:42647–42654
22. Rosenberg MF, Kamis AB, Aleksandrov LA, Ford RC, Riordan JR (2004) Purification and crystallization of the cystic fibrosis transmembrane conductance regulator (CFTR). J Biol Chem 279:39051–39057
23. Mio K, Ogura T, Mio M, Shimizu H, Hwang TC, Sato C et al (2008) Three-dimensional reconstruction of human cystic fibrosis transmembrane conductance regulator chloride channel revealed an ellipsoidal structure with orifices beneath the putative transmembrane domain. J Biol Chem 283:30300–30310
24. Awayn NH, Rosenberg MF, Kamis AB, Aleksandrov LA, Riordan JR, Ford RC (2005) Crystallographic and single-particle analyses of native- and nucleotide-bound forms of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Biochem Soc Trans 33:996–999
25. Atwell S, Brouillette CG, Conners K, Emtage S, Gheyi T, Guggino WB et al (2010) Structures of a minimal human CFTR first nucleotide-binding domain as a monomer, head-to-tail homodimer, and pathogenic mutant. Protein Eng Des Sel 23:375–384
26. Lewis HA, Buchanan SG, Burley SK, Conners K, Dickey M, Dorwart M et al (2004) Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO J 23:282–293
27. Lewis HA, Wang C, Zhao X, Hamuro Y, Conners K, Kearins MC et al (2010) Structure and dynamics of NBD1 from CFTR characterized using crystallography and hydrogen/deuterium exchange mass spectrometry. J Mol Biol 396:406–430
28. Lewis HA, Zhao X, Wang C, Sauder JM, Rooney I, Noland BW et al (2005) Impact of the deltaF508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure. J Biol Chem 280:1346–1353
29. Thibodeau PH, Brautigam CA, Machius M, Thomas PJ (2005) Side chain and backbone contributions of Phe508 to CFTR folding. Nat Struct Mol Biol 12:10–16
30. Kanelis V, Hudson RP, Thibodeau PH, Thomas PJ, Forman-Kay JD (2010) NMR evidence for differential phosphorylation-dependent interactions in WT and DeltaF508 CFTR. EMBO J 29:263–277
31. Hudson RP, Chong PA, Protasevich II, Vernon R, Noy E, Bihler H et al (2012) Conformational changes relevant to channel activity and folding within the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 287:28480–28494
32. Dawson JE, Farber PJ, Forman-Kay JD (2013) Allosteric coupling between the intracellular coupling helix 4 and regulatory sites of the first nucleotide-binding domain of CFTR. PLoS One 8:e74347
33. Chong PA, Farber PJ, Vernon RM, Hudson RP, Mittermaier AK, Forman-Kay JD (2015) Deletion of phenylalanine 508 in the first nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator increases conformational exchange and inhibits dimerization. J Biol Chem 290:22862–22878
34. Baker JM, Hudson RP, Kanelis V, Choy WY, Thibodeau PH, Thomas PJ et al (2007) CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. Nat Struct Mol Biol 14:738–745
35. Galeno L, Galfrè E, Moran O (2011) Small-angle X-ray scattering study of the ATP modulation of the structural features of the nucleotide binding domains of the CFTR in solution. Eur Biophys J 40:811–824
36. Galfrè E, Galeno L, Moran O (2012) A potentiator induces conformational changes on the recombinant CFTR nucleotide binding domains in solution. Cell Mol Life Sci 69:3701–3713
37. Marasini C, Galeno L, Moran O (2013) A SAXS-based ensemble model of the native and phosphorylated regulatory domain of the CFTR. Cell Mol Life Sci 70:923–933
38. Pollock NL, Satriano L, Zegarra-Moran O, Ford RC, Moran O (2016) Structure of wild type and mutant F508del CFTR: a small-angle X-ray scattering study of the protein-detergent complexes. J Struct Biol 194:102–111
39. Moran O (2014) On the structural organization of the intracellular domains of CFTR. Int J Biochem Cell Biol 52:7–14
40. Odolczyk N, Zielenkiewicz P (2014) Molecular modelling approaches for cystic fibrosis transmembrane conductance regulator studies. Int J Biochem Cell Biol 52:39–46
41. Belmonte L, Moran O (2015) On the interactions between nucleotide binding domains and membrane spanning domains in cystic fibrosis transmembrane regulator: a molecular dynamic study. Biochimie 111:19–29
42. Corradi V, Vergani P, Tieleman DP (2015) Cystic fibrosis transmembrane conductance regulator (CFTR): closed and open state channel models. J Biol Chem 290:22891–22906
43. Mornon J-P, Hoffmann B, Jonic S, Lehn P, Callebaut I (2015) Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics. Cell Mol Life Sci 72:1377–1403
44. Zhenin M, Noy E, Senderowitz H (2015) REMD simulations reveal the dynamic profile and mechanism of action of deleterious, rescuing, and stabilizing perturbations to NBD1 from CFTR. J Chem Inf Model 55:2349–2364
45. Schmitt L, Tampé R (2002) Structure and mechanism of ABC transporters. Curr Opin Struct Biol 12:754–760
46. Callebaut I, Eudes R, Mornon J-P, Lehn P (2004) Nucleotide-binding domains of human cystic fibrosis transmembrane conductance regulator: detailed sequence analysis and three-dimensional modeling of the heterodimer. Cell Mol Life Sci 61:230–242
47. Eudes R, Lehn P, Férec C, Mornon J-P, Callebaut I (2005) Nucleotide binding domains of human CFTR: a structural classification of critical residues and disease-causing mutations. Cell Mol Life Sci 62:2112–2123
48. Smith PC, Karpowich N, Millen L, Moody JE, Rosen J, Thomas PJ et al (2002) ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer. Mol Cell 10:139–149
49. Kidd JF, Ramjeesingh M, Stratford F, Huan LJ, Bear CE (2004) A heteromeric complex of the two nucleotide binding domains of cystic fibrosis transmembrane conductance regulator (CFTR) mediates ATPase activity. J Biol Chem 279:41664–41669
50. Mense M, Vergani P, White DM, Altberg G, Nairn AC, Gadsby DC (2006) In vivo phosphorylation of CFTR promotes formation of a nucleotide-binding domain heterodimer. EMBO J 25:4728–4739
51. Stratford FL, Ramjeesingh M, Cheung JC, Huan LJ, Bear CE (2007) The Walker B motif of the second nucleotide-binding domain (NBD2) of CFTR plays a key role in ATPase activity by the NBD1–NBD2 heterodimer. Biochem J 401:581–586
52. Vergani P, Lockless SW, Nairn AC, Gadsby DC (2005) CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains. Nature 433:876–880
53. Ramjeesingh M, Li C, Garami E, Huan LJ, Galley K, Wang Y et al (1999) Walker mutations reveal loose relationship between catalytic and channel-gating activities of purified CFTR (cystic fibrosis transmembrane conductance regulator). Biochemistry 38:1463–1468
54. Aleksandrov L, Aleksandrov AA, Chang XB, Riordan JR (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
55. Basso C, Vergani P, Nairn AC, Gadsby DC (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
56. Zhou Z, Wang X, Liu HY, Zou X, Li M, Hwang TC (2006) The two ATP binding sites of cystic fibrosis transmembrane conductance regulator (CFTR) play distinct roles in gating kinetics and energetics. J Gen Physiol 128:413–422
57. Procko E, Ferrin-O’Connell I, Ng SL, Gaudet R (2006) Distinct structural and functional properties of the ATPase sites in an asymmetric ABC transporter. Mol Cell 24:51–62
58. Szollosi A, Muallem DR, Csanády L, Vergani P (2011) Mutant cycles at CFTR’s non-canonical ATP-binding site support little interface separation during gating. J Gen Physiol 137:549–562
59. Tsai MF, Li M, Hwang TC (2010) Stable ATP binding mediated by a partial NBD dimer of the CFTR chloride channel. J Gen Physiol 135:399–414
60. Protasevich I, Yang Z, Wang C, Atwell S, Zhao X, Emtage S et al (2010) Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1. Protein Sci 19:1917–1931
61. Wang C, Protasevich I, Yang Z, Seehausen D, Skalak T, Zhao X et al (2010) Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis. Protein Sci 19:1932–1947
62. Aleksandrov AA, Kota P, Aleksandrov LA, He L, Jensen T, Cui L et al (2010) Regulatory insertion removal restores maturation, stability and function of DeltaF508 CFTR. J Mol Biol 401:194–210
63. Moran O, Galietta LJ, Zegarra-Moran O (2005) Binding site of activators of the cystic fibrosis transmembrane conductance regulator in the nucleotide binding domains. Cell Mol Life Sci 62:446–460
64. Huang S-Y, Bolser D, Liu H-Y, Hwang TC (2009) Molecular modeling of the heterodimer of human CFTR’s nucleotide-binding domains using a protein–protein docking approach. J Mol Graph Model 27:822–828
65. Dawson RJ, Locher KP (2006) Structure of a bacterial multidrug ABC transporter. Nature 443:180–185
66. Dawson RJ, Locher KP (2007) Structure of the multidrug ABC transporter Sav 1866 from Staphylococcus aureus in complex with AMP–PNP. FEBS Lett 581:935–938
67. Ward A, Reyes CL, Yu J, Roth CB, Chang G (2007) Flexibility in the ABC transporter MsbA: alternating access with a twist. Proc Natl Acad Sci USA 104:19005–19010
68. Mornon J-P, Lehn P, Callebaut I (2008) Atomic model of human cystic fibrosis transmembrane conductance regulator: membrane-spanning domains and coupling interfaces. Cell Mol Life Sci 65:2594–2612
69. Mornon J-P, Lehn P, Callebaut I (2009) Molecular models of the open and closed states of the whole human CFTR protein. Cell Mol Life Sci 66:3469–3486
70. Serohijos AW, Hegedus T, Aleksandrov AA, He L, Cui L, Dokholyan NV et al (2008) Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Proc Natl Acad Sci USA 105:3256–3261
71. Hegedűs T, Serohijos AW, Dokholyan NV, He L, Riordan JR (2008) Computational studies reveal phosphorylation-dependent changes in the unstructured R domain of CFTR. J Mol Biol 378:1052–1063
72. He L, Aleksandrov AA, Serohijos AW, Hegedus T, Aleksandrov LA, Cui L et al (2008) Multiple membrane-cytoplasmic domain contacts in the cystic fibrosis transmembrane conductance regulator (CFTR) mediate regulation of channel gating. J Biol Chem 283:26383–26390
73. Higgins CF, Linton KJ (2004) The ATP switch model for ABC transporters. Nat Struct Mol Biol 11:918–926
74. Jones PM, George AM (2014) A reciprocating twin-channel model for ABC transporters. Q Rev Biophys 47:189–220
75. Linsdell P (2014) Functional architecture of the CFTR chloride channel. Mol Membr Biol 31:1–16
76. Cai Z, Scott-Ward TS, Sheppard DN (2003) Voltage-dependent gating of the cystic fibrosis transmembrane conductance regulator Cl-channel. J Gen Physiol 122:605–620
77. Da Paula AC, Sousa M, Xu Z, Dawson ES, Boyd AC, Sheppard DN et al (2010) Folding and rescue of a cystic fibrosis transmembrane conductance regulator trafficking mutant identified using human-murine chimeric proteins. J Biol Chem 285:27033–27044
78. Norimatsu Y, Ivetac A, Alexander C, O’Donnell N, Frye L, Sansom MS et al (2012) Locating a plausible binding site for an open-channel blocker, GlyH-101, in the pore of the cystic fibrosis transmembrane conductance regulator. Mol Pharmacol 82:1042–1055
79. Alexander C, Ivetac A, Liu X, Norimatsu Y, Serrano JR, Landstrom A et al (2009) Cystic fibrosis transmembrane conductance regulator: using differential reactivity toward channel-permeant and channel-impermeant thiol-reactive probes to test a molecular model for the pore. Biochemistry 48:10078–10088
80. Dalton J, Kalid O, Schushan M, Ben-Tal N, Villà-Freixa J (2012) New model of cystic fibrosis transmembrane conductance regulator proposes active channel-like conformation. J Chem Inf Model 52:1842–1853
81. Chen EY, Bartlett MC, Loo TW, Clarke DM (2004) The DeltaF508 mutation disrupts packing of the transmembrane segments of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 279:39620–39627
82. Gao X, Hwang TC (2016) Spatial positioning of CFTR’s pore-lining residues affirms an asymmetrical contribution of transmembrane segments to the anion permeation pathway. J Gen Physiol 147:407–422
83. Wang W, El Hiani Y, Rubaiy HN, Linsdell P (2014) Relative contribution of different transmembrane segments to the CFTR chloride channel pore. Pflugers Arch 466:477–490
84. Wang W, El Hiani Y, Linsdell P (2011) Alignment of transmembrane regions in the cystic fibrosis transmembrane conductance regulator chloride channel pore. J Gen Physiol 138:165–178
85. Quian F, El Hiani Y, Linsdell P (2011) Functional arrangement of the 12th transmembrane region in the CFTR chloride channel pore based on functional investigation of a cysteine-less CFTR variant. Eur J Physiol 462:559–571
86. McCarty NA, Zhang ZR (2001) Identification of a region of strong discrimination in the pore of CFTR. Am J Physiol Lung Cell Mol Physiol 281:L852–L867
87. Gupta J, Evagelidis A, Hanrahan JW, Linsdell P (2001) Asymmetric structure of the cystic fibrosis transmembrane conductance regulator chloride channel pore suggested by mutagenesis of the twelfth transmembrane region. Biochemistry 40:6620–6627
88. Ge N, Muise CN, Gong X, Linsdell P (2004) Direct comparison of the functional roles played by different transmembrane regions in the cystic fibrosis transmembrane conductance regulator chloride channel pore. J Biol Chem 279:55283–55289
89. Gao X, Bai Y, Hwang TC (2013) Cysteine scanning of CFTR’s first transmembrane segment reveals its plausible roles in gating and permeation. Biophys J 104:786–797
90. Fatehi M, Linsdell P (2009) Novel residues lining the CFTR chloride channel pore identified by functional modification of introduced cysteines. J Membr Biol 228:151–164
91. Cui G, Song B, Turki HW, McCarty NA (2012) Differential contribution of TM6 and TM12 to the pore of CFTR identified by three sulfonylurea-based blockers. Pflugers Arch 463:405–418
92. Cheung M, Akabas MH (1996) Identification of cystic fibrosis transmembrane conductance regulator channel-lining residues in and flanking the M6 membrane-spanning segment. Biophys J 70:2688–2699
93. Bai Y, Li M, Hwang TC (2011) Structural basis for the channel function of a degraded ABC transporter, CFTR (ABCC7). J Gen Physiol 138:495–507
94. Bai Y, Li M, Hwang TC (2010) Dual roles of the sixth transmembrane segment of the CFTR chloride channel in gating and permeation. J Gen Physiol 136:293–309
95. Akabas MH, Kaufmann C, Cook TA, Archdeacon P (1994) Amino acid residues lining the chloride channel of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 269:14865–14868
96. Beck EJ, Yang Y, Yaemsiri S, Raghuram V (2008) Conformational changes in a pore-lining helix coupled to cystic fibrosis transmembrane conductance regulator channel gating. J Biol Chem 283:4957–4966
97. El Hiani Y, Linsdell P (2010) Changes in accessibility of cytoplasmic substances to the pore associated with activation of the cystic fibrosis transmembrane conductance regulator chloride channel. J Biol Chem 285:32126–32140
98. Qian F, Liu L, Liu Z, Lu C (2016) The pore architecture of the cystic fibrosis transmembrane conductance regulator channel revealed by co-mutation in pore-forming transmembrane regions. Physiol Res 65:505–515
99. Cui G, Freeman CS, Knotts T, Prince CZ, Kuang C, McCarty NA (2013) Two salts bridges differentially contribute to the maintenance of cystic fibrosis transmembrane conductance regulator (CFTR) channel function. J Biol Chem 288:20758–20767
100. Rahman KS, Cui G, Harvey SC, McCarty NA (2013) Modeling the conformational changes underlying channel opening in CFTR. PLoS One 8:e74574
101. Cui G, Khazanov N, Stauffer B, Infield DT, Imhoff BR, Senderowitz H et al (2016) Potentiators exert distinct effects on human, murine, and Xenopus CFTR. Am J Physiol Lung Cell Mol Physiol 311:L192–L207
102. Infield DT, Cui G, Kuang C, McCarty NA (2016) Positioning of extracellular loop 1 affects pore gating of the cystic fibrosis transmembrane conductance regulator. Am J Physiol Lung Cell Mol Physiol 310:L403–L414
103. Billet A, Mornon J-P, Jollivet M, Lehn P, Callebaut I, Becq F (2013) CFTR: effect of ICL2 and ICL4 amino acids in close spatial proximity on the current properties of the channel. J Cyst Fibros 12:737–745
104. Wang W, Roessler BC, Kirk KL (2014) An electrostatic interaction at the tetrahelix bundle promotes phosphorylation-dependent cystic fibrosis transmembrane conductance regulator (CFTR) channel opening. J Biol Chem 289:30364–30378
105. Linsdell P (2016) Anion conductance selectivity mechanism of the CFTR chloride channel. Biochim Biophys Acta 1858:740–747
106. Gao X, Hwang TC (2015) Localizing a gate in CFTR. Proc Natl Acad Sci USA 112:2461–2466
107. Wei S, Roessler BC, Icyuz M, Chauvet S, Tao B, Hartman JLT et al (2016) Long-range coupling between the extracellular gates and the intracellular ATP binding domains of multidrug resistance protein pumps and cystic fibrosis transmembrane conductance regulator channels. FASEB J 30:1247–1262
108. Wei S, Roessler BC, Chauvet S, Guo J, Hartman JL, Kirk KL (2014) Conserved allosteric hot spots in the transmembrane domains of cystic fibrosis transmembrane conductance regulator (CFTR) channels and multidrug resistance protein (MRP) pumps. J Biol Chem 289:19942–19957
109. Mihályi C, Töröcsik B, Csanády L (2016) Obligate coupling of CFTR pore opening to tight nucleotide-binding domain dimerization. Elife 5:e18164
110. Gadsby DC (2009) Ion channels versus ion pumps: the principal difference, in principle. Nat Rev Mol Cell Biol 10:344–352
111. Payandeh J, Scheuer T, Zheng N, Catterall WA (2011) The crystal structure of a voltage-gated sodium channel. Nature 475:353–358
112. Samways DS, Khakh BS, Dutertre S, Egan TM (2011) Preferential use of unobstructed lateral portals as the access route to the pore of human ATP-gated ion channels (P2X receptors). Proc Natl Acad Sci USA 108:13800–13805
113. El Hiani Y, Linsdell P (2015) Functional architecture of the cytoplasmic entrance to the cystic fibrosis transmembrane conductance regulator chloride channel pore. J Biol Chem 290:15855–15865
114. El Hiani Y, Negoda A, Linsdell P (2016) Cytoplasmic pathway followed by chloride ions to enter the CFTR channel pore. Cell Mol Life Sci 73:1917–1925
115. Furukawa-Hagiya T, Furuta T, Chiba S, Sohma Y, Sakurai M (2013) The power stroke driven by ATP binding in CFTR as studied by molecular dynamics simulations. J Phys Chem B 117:83–93
116. Choudhury HG, Tong Z, Mathavan I, Li Y, Iwata S, Zirah S et al (2014) Structure of an antibacterial peptide ATP-binding cassette transporter in a novel outward occluded state. Proc Natl Acad Sci USA 111:9145–9150
117. Lin DY, Huang S, Chen J (2015) Crystal structures of a polypeptide processing and secretion transporter. Nature 523:425–430
118. Kim J, Wu S, Tomasiak TM, Mergel C, Winter MB, Stiller SB et al (2015) Subnanometre-resolution electron cryomicroscopy structure of a heterodimeric ABC exporter. Nature 517:396–400
119. Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R et al (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323:1718–1722
120. Ward AB, Szewczyk P, Grimard V, Lee CW, Martinez L, Doshi R 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
121. Li J, Jaimes KF, Aller SG (2014) Refined structures of mouse P-glycoprotein. Protein Sci 23:34–46
122. Jin MS, Oldham ML, Zhang Q, Chen J (2012) Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. Nature 490:566–569
123. Kodan A, Yamaguchi T, Nakatsu T, Sakiyama K, Hipolito CJ, Fujioka A, Hirokane R, Ikeguchi K, Watanabe B, Hiratake J, Kimura Y, Suga H, Ueda K, Kato H (2014) Structural basis for gating mechanisms of a eukaryotic P-glycoprotein homolog. Proc Natl Acad Sci 111(11):4049–4054
124. Srinivasan V, Pierik AJ, Lill R (2014) Crystal structures of nucleotide-free and glutathione-bound mitochondrial ABC transporter Atm1. Science 343:1137–1140
125. Lee JY, Yang JG, Zhitnitsky D, Lewinson O, Rees DC (2014) Structural basis for heavy metal detoxification by an Atm1-type ABC exporter. Science 343:1133–1136
126. Shintre CA, Pike AC, Li Q, Kim JI, Barr A, Goubin S 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
127. Perez C, Gerber S, Boilevin J, Bucher M, Darbre T, Aebi M et al. (2015) Structure and mechanism of an active lipid-linked oligosaccharide flippase. Nature 524:433–438
128. Hohl M, Briand C, Grütter MG, Seeger MA (2012) Crystal structure of a heterodimeric ABC transporter in its inward-facing conformation. Nat Struct Mol Biol 19:395–402
129. Hohl M, Hürlimann LM, Böhm S, Schöppe J, Grütter MG, Bordignon E et al (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
130. Jones PM, George AM (2012) Role of the D-loops in allosteric control of ATP hydrolysis in an ABC transporter. J Phys Chem A 116:3004–3013
131. Liu J, Cami-Kobeci G, Wang Y, Kuituan P, Cai Z, Li H et al (2014) The therapeutic potential of small-molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl-channel. In: Cox B, Gosling M (eds) Ion channel drug discovery, Royal Society of Chemistry, pp 156–185
132. Farinha CM, Matos P (2016) Repairing the basic defect in cystic fibrosis—one approach is not enough. FEBS J 283:246–264
133. Lukacs GL, Verkman AS (2012) CFTR: folding, misfolding and correcting the DeltaF508 conformational defect. Trends Mol Med 18:81–91
134. Lazrak A, Fu L, Bal IV, Bartoszewski R, Rab A, Havasi V et al (2013) The silent codon change I507-ATC → ATT contributes to the severity of the ΔF508 CFTR channel dysfunction. FASEB J 27:4630–4645
135. Thibodeau PH, Richardson JMr, Wang W, Millen L, Watson J, Mendoza JL et al (2010) The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis. J Biol Chem 285:35825–35835
136. Rabeh WM, Bossard F, Xu H, Okiyoneda T, Bagdany M, Mulvihill CM et al (2012) Correction of both NBD1 energetics and domain interface is required to restore ΔF508 CFTR folding and function. Cell 148:150–163
137. Mendoza JL, Schmidt A, Li Q, Nuvaga E, Barrett T, Bridges RJ et al (2012) Requirements for efficient correction of DF508 CFTR revealed by analyses of evolved sequences. Cell 148:164–174
138. Rosser MF, Grove DE, Chen L, Cyr DM (2008) Assembly and misassembly of cystic fibrosis transmembrane conductance regulator: folding defects caused by deletion of F508 occur before and after the calnexin-dependent association of membrane spanning domain (MSD) 1 and MSD2. Mol Biol Cell 19:4570–4579
139. Cui L, Aleksandrov L, Chang XB, Hou YX, He L, Hegedus T et al (2007) Domain interdependence in the biosynthetic assembly of CFTR. J Mol Biol 365:981–994
140. He L, Aleksandrov LA, Cui L, Jensen TJ, Nesbitt KL, Riordan JR (2010) Restoration of domain folding and interdomain assembly by second-site suppressors of the DeltaF508 mutation in CFTR. FASEB J 24:3103–3112
141. Du K, Sharma M, Lukacs GL (2005) The DeltaF508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR. Nat Struct Mol Biol 12:17–25
142. He L, Aleksandrov AA, An J, Cui L, Yang Z, Brouillette CG et al (2015) Restoration of NBD1 thermal stability is necessary and sufficient to correct DF508 CFTR folding and assembly. J Mol Biol 427:106–120
143. He L, Kota P, Aleksandrov AA, Cui L, Jensen T, Dokholyan NV et al (2013) Correctors of ΔF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein. FASEB J 27:536–545
144. Warner DJ, Vadolia MM, Laughton CA, Kerr ID, Doughty SW (2007) Modelling the restoration of wild-type dynamic behaviour in DeltaF508-CFTR NBD1 by 8-cyclopentyl-1,3-dipropylxanthine. J Mol Graph Model 26:691–699
145. Wieczorek G, Zielenkiewicz P (2008) DeltaF508 mutation increases conformational flexibility of CFTR protein. J Cyst Fibros 7:295–300
146. Bisignano P, Moran O (2010) Molecular dynamics analysis of the wild type and dF508 mutant structures of the human CFTR-nucleotide binding domain 1. Biochimie 92:51–57
147. Serohijos AW, Hegedus T, Riordan JR, Dokholyan NV (2008) Diminished self-chaperoning activity of the DeltaF508 mutant of CFTR results in protein misfolding. PLoS Comput Biol 4:e1000008
148. Proctor EA, Kota P, Aleksandrov AA, He L, Riordan JR, Dokholyan NV (2015) Rational coupled dynamics network manipulation rescues disease-relevant mutant cystic fibrosis transmembrane conductance regulator. Chem Sci 6:1237–1246
149. Loo TW, Barlett MC, Clarke DM (2010) The V510D suppressor mutation stabilizes DeltaF508-CFTR at the cell surface. Biochemistry 49:6352–6357
150. Aleksandrov AA, Kota P, Cui L, Jensen T, Alekseev AE, Reyes S et al (2012) Allosteric modulation balances thermodynamic stability and restores function of DF508 CFTR. J Mol Biol 419:41–60
151. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P et al (2011) A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 365:1663–1672
152. Lin WY, Jih KY, Hwang TC (2014) A single amino acid substitution in CFTR converts ATP to an inhibitory ligand. J Gen Physiol 144(4):311–320
153. Eckford PD, Ramjeesingh M, Molinski S, Pasyk S, Dekkers JF, Li C et al (2014) VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial rescue to the cell surface. Chem Biol 21:666–678
154. Sampson HM, Robert R, Liao J, Matthes E, Carlile GW, Hanrahan JW et al (2011) Identification of a NBD1-binding pharmacological chaperone that corrects the trafficking defect of F508del-CFTR. Chem Biol 18:231–242
155. Eckford PD, Li C, Ramjeesingh M, Bear CE (2012) Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem 287:36639–36649
156. Jih KY, Hwang TC (2013) Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Proc Natl Acad Sci USA 110:4404–4409
157. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T et al (2009) Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA 106:18825–18830
158. Yu H, Burton B, Huang CJ, Worley J, Cao D, Johnson JPJ et al (2012) Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros 11:237–245
159. Yeh HI, Yeh JT, Hwang TC (2015) Modulation of CFTR gating by permeant ions. J Gen Physiol 145:47–60
160. Linsdell P (2014) State-dependent blocker interactions with the CFTR chloride channel: implications for gating the pore. Pflugers Arch 466:2243–2255
161. Csanády L, Töröcsik B (2014) Catalyst-like modulation of transition states for CFTR channel opening and closing: new stimulation strategy exploits nonequilibrium gating. J Gen Physiol 143:269–287
162. Csanády L, Töröcsik B (2014) Structure-activity analysis of a CFTR channel potentiator: distinct molecular parts underlie dual gating effects. J Gen Physiol 144:321–336
163. Kalid O, Mense M, Fischman S, Shitrit A, Bihler H, Ben-Zeev E et al (2010) Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening. J Comput Aided Mol Des 24:971–991
164. Odolczyk N, Fritsch J, Norez C, Servel N, da Cunha MF, Bitam S et al (2013) Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain. EMBO Mol Med 5:1484–1501
165. Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M et al (2015) Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 373:220–231
166. Elborn JS, Ramsey BW, Boyle MP, Konstan MW, Huang X, Marigowda G et al (2016) Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis. Lancet Respir Med 4:617–626
167. Farinha CM, King-Underwood J, Sousa M, Correia AR, Henriques BJ, Roxo-Rosa M et al (2013) Revertants, low temperature, and correctors reveal the mechanism of F508del-CFTR rescue by VX-809 and suggest multiple agents for full correction. Chem Biol 20:943–955
168. Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H et al (2013) Mechanism-based corrector combination restores DF508-CFTR folding and function. Nat Chem Biol 9:444–454
169. Ren HY, Grove DE, Houck SA, Sopha P, van Goor F, Hoffman BJ et al (2013) VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell 24:3016–3024
170. Loo TW, Bartlett MC, Clarke DM (2013) Corrector VX-809 stabilizes the first transmembrane domain of CFTR. Biochem Pharmacol 86:612–619
171. Veit G, Avramescu RG, Perdomo D, Phuan PW, Bagdany M, Apaja PM, Borot F, Szollosi D, Wu YS, Finkbeiner WE, Hegedus T, Verkman AS, Lukacs GL (2014) Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression. Sci Transl Med 6(246):246ra97
172. Cholon DM, Quinney NL, Fulcher ML, Esther CR Jr, Das J, Dokholyan NV, Randell SH, Boucher RC, Gentzsch M (2014) Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis. Sci Transl Med 6(246):246ra96
173. Phuan PW, Veit G, Tan JA, Finkbeiner WE, Lukacs GL, Verkman AS (2015) Potentiators of defective ΔF508-CFTR gating that do not interfere with corrector action. Mol Pharmacol 88:791–799
174. Phuan PW, Veit G, Tan J, Roldan A, Finkbeiner WE, Lukacs GL et al (2014) Synergy-based small-molecule screen using a human lung epithelial cell line yields ΔF508-CFTR correctors that augment VX-809 maximal efficacy. Mol Pharmacol 86:42–51
175. Pesce E, Bellotti M, Liessi N, Guariento S, Damonte G, Cichero E et al (2015) Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis. Eur J Med Chem 99:14–35
176. Pedemonte N, Lukacs GL, Du K, Caci E, Zegarra-Moran O, Galietta LJ et al (2005) Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. J Clin Invest 115:2564–2571
177. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS et al (2011) Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA 108:18843–18848
178. Loo TW, Bartlett MC, Clarke DM (2013) Bithiazole correctors rescue CFTR mutants by two different mechanisms. Biochemistry 52:5161–5163
179. Wang Y, Loo TW, Bartlett MC, Clarke DM (2007) Correctors promote maturation of cystic fibrosis transmembrane conductance regulator (CFTR)-processing mutants by binding to the protein. J Biol Chem 282:33247–33251
180. Grove DE, Rosser MF, Ren HY, Naren AP, Cyr DM (2009) Mechanisms for rescue of correctable folding defects in CFTRDelta F508. Mol Biol Cell 20:4059–4069
181. Roberts KE, Cushing PR, Boisguerin P, Madden DR, Donald BR (2012) Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity. PLoS Comput Biol 8:e1002477
182. Hall JD, Wang H, Byrnes LJ, Shanker S, Wang K, Efremov IV et al (2016) Binding screen for cystic fibrosis transmembrane conductance regulator correctors finds new chemical matter and yields insights into cystic fibrosis therapeutic strategy. Protein Sci 25:360–373
183. Faure G, Bakouh N, Lourdel S, Odolczyk N, Premchandar A, Servel N et al (2016) Rattlesnake phospholipase A2 increases CFTR-chloride channel current and corrects ∆F508CFTR dysfunction: impact in cystic fibrosis. J Mol Biol 428:2898–2915
184. Thiagarajah JR, Ko EA, Tradtrantip L, Donowitz M, Verkman AS (2014) Discovery and development of antisecretory drugs for treating diarrheal diseases. Clin Gastroenterol Hepatol 12:204–209
185. Li H, Sheppard D (2009) Therapeutic potential of cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors in polycystic kidney disease. BioDrugs 23:203–216
186. Linsdell P (2014) Cystic fibrosis transmembrane conductance regulator chloride channel blockers: pharmacological, biophysical and physiological relevance. World J Biol Chem 5:26–39
187. Kim Y, Anderson MO, Park J, Lee MG, Namkung W, Verkman AS (2015) Benzopyrimido-pyrrolo-oxazine-dione (R)-BPO-27 inhibits CFTR chloride channel gating by competition with ATP. Mol Pharmacol 88:689–696
188. Linsdell P (2005) Location of a common inhibitor binding site in the cytoplasmic vestibule of the cystic fibrosis transmembrane conductance regulator chloride channel pore. J Biol Chem 280:8945–8950
189. St Aubin CN, Zhou JJ, Linsdell P (2007) Identification of a second blocker binding site at the cytoplasmic mouth of the cystic fibrosis transmembrane conductance regulator chloride channel pore. Mol Pharmacol 71:1360–1368
190. Kopeikin Z, Sohma Y, Li M, Hwang TC (2010) On the mechanism of CFTR inhibition by a thiazolidinone derivative. J Gen Physiol 136:659–671
191. Caci E, Caputo A, Hinzpeter A, Arous N, Fanen P, Sonawane N et al (2008) Evidence for direct CFTR inhibition by CFTRinh-172 based on Arg347 mutagenesis. Biochem J 413:135–142
192. Stahl M, Stah lK, Brubacher MB, Forrest JNJ (2012) Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101. Am J Physiol Cell Physiol 302:C67–C76
193. Noy E, Senderowitz H (2011) Combating cystic fibrosis: in search for CF transmembrane conductance regulator (CFTR) modulators. ChemMedChem 6:243–251
194. Kleizen B, van Vlijmen T, de Jonge HR, Braakman I (2005) Folding of CFTR is predominantly cotranslational. Mol Cell 20:277–287
195. Hoelen H, Kleizen B, Schmidt A, Richardson J, Charitou P, Thomas PJ et al (2010) The primary folding defect and rescue of ΔF508 CFTR emerge during translation of the mutant domain. PLoS One 5:e15458
196. McClure M, DeLucas LJ, Wilson L, Ray M, Rowe SM, Wu X et al (2012) Purification of CFTR for mass spectrometry analysis: identification of palmitoylation and other post-translational modifications. Protein Eng Des Sel 25:7–14
197. Bai XC, McMullan G, Scheres SH (2015) How cryo-EM is revolutionizing structural biology. Trends Biochem Sci 40:49–57
198. Nogales E, Scheres SH (2015) Cryo-EM: a unique tool for the visualization of macromolecular complexity. Mol Cell 58:677–689
199. Cant N, Pollock N, Ford RC (2014) CFTR structure and cystic fibrosis. Int J Biochem Cell Biol 52:15–25
200. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC et al (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612