Skip to main content
SpringerLink
Log in

Combining theoretical and experimental data to decipher CFTR 3D structures and functions

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Cryo-electron microscopy (cryo-EM) has recently provided invaluable experimental data about the full-length cystic fibrosis transmembrane conductance regulator (CFTR) 3D structure. However, this experimental information deals with inactive states of the channel, either in an apo, quiescent conformation, in which nucleotide-binding domains (NBDs) are widely separated or in an ATP-bound, yet closed conformation. Here, we show that 3D structure models of the open and closed forms of the channel, now further supported by metadynamics simulations and by comparison with the cryo-EM data, could be used to gain some insights into critical features of the conformational transition toward active CFTR forms. These critical elements lie within membrane-spanning domains but also within NBD1 and the N-terminal extension, in which conformational plasticity is predicted to occur to help the interaction with filamin, one of the CFTR cellular partners.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Cheng SH, Gregory RJ, Marshall J, Paul S, Souza DW, White GA, O’Riordan CR, Smith AE (1990) Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63:827–834

    Article  CAS  Google Scholar 

  2. Gadsby DC (2009) Ion channels versus ion pumps: the principal difference, in principle. Nat Rev Mol Cell Biol 10:344–352

    Article  CAS  Google Scholar 

  3. Aleksandrov LA, Jensen TJ, Cui L, Kousouros JN, He L, Aleksandrov AA, Riordan JR (2015) Thermal stability of purified and reconstituted CFTR in a locked open channel conformation. Protein Expr Purif 116:159–166

    Article  CAS  Google Scholar 

  4. 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

    Article  CAS  Google Scholar 

  5. Callebaut I, Hoffmann B, Mornon J-P (2017) The implications of CFTR structural studies for cystic fibrosis drug development. Curr Opin Pharmacol 34:112–118

    Article  CAS  Google Scholar 

  6. Zhang Z, Chen J (2016) Atomic structure of the cystic fibrosis transmembrane conductance regulator. Cell 167:1586–1597

    Article  CAS  Google Scholar 

  7. Liu F, Zhang Z, Csanády L, Gadsby DC, Chen J (2017) Molecular structure of the human CFTR ion channel. Cell 169:85–95

    Article  CAS  Google Scholar 

  8. Zhang Z, Liu F, Chen J (2017) Conformational changes of CFTR upon phosphorylation and ATP binding. Cell 170:483–491

    Article  CAS  Google Scholar 

  9. Tordai H, Leveles I, Hegedus T (2017) Molecular dynamics of the cryo-EM CFTR structure. Biochem Biophys Res Commun 491:986–993

    Article  CAS  Google Scholar 

  10. Corradi V, Gu R-X, Vergani P, Tieleman D (2018) Structure of transmembrane helix 8 and possible membrane defects in CFTR. Biophys J 114:1751–1754

    Article  CAS  Google Scholar 

  11. Callebaut I, Hoffmann B, Lehn P, Mornon J-P (2017) Molecular modelling and molecular dynamics of CFTR. Cell Mol Life Sci 74:3–22

    Article  CAS  Google Scholar 

  12. 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

    Article  CAS  Google Scholar 

  13. Norimatsu Y, Ivetac A, Alexander C, O’Donnell N, Frye L, Sansom MS, Dawson DC (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

    Article  CAS  Google Scholar 

  14. 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

    Article  CAS  Google Scholar 

  15. 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

    Article  CAS  Google Scholar 

  16. Das J, Aleksandrov AA, Cui L, He L, Riordan JR, Dokholyan NV (2017) Transmembrane helical interactions in the CFTR channel pore. PLoS Comput Biol 13:e1005594

    Article  Google Scholar 

  17. Linsdell P (2014) Functional architecture of the CFTR chloride channel. Mol Membr Biol 31:1–16

    Article  CAS  Google Scholar 

  18. 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

    Article  CAS  Google Scholar 

  19. Cui G, Zhang ZR, O’Brien AR, Song B, McCarty NA (2008) Mutation at arginine 352 alters the pore architecture of CFTR. J Membr Biol 222:91–106

    Article  CAS  Google Scholar 

  20. Cotten JF, Welsh MJ (1999) Cystic fibrosis-associated mutations at arginine 347 alter the pore architecture of CFTR. Evidence for disruption of a salt bridge. J Biol Chem 274:5429–5435

    Article  CAS  Google Scholar 

  21. 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

    Article  Google Scholar 

  22. 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

    Article  Google Scholar 

  23. Gao X, Hwang TC (2015) Localizing a gate in CFTR. Proc Natl Acad Sci USA 112:2461–2466

    Article  CAS  Google Scholar 

  24. Negoda A, El Hiani Y, Cowley EA, Linsdell P (2017) Contribution of a leucine residue in the first transmembrane segment to the selectivity filter region in the CFTR chloride channel. Biochem Biophys Acta 1859:1049–1058

    Article  CAS  Google Scholar 

  25. Marti-Renom MA, Stuart A, Fiser A, Sánchez R, Melo F, Sali A (2000) Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct 29:291–325

    Article  CAS  Google Scholar 

  26. Brooks BR, Brooks CL, Mackerell AD, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S et al (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30:1545–1614

    Article  CAS  Google Scholar 

  27. Jo S, Kim T, Iyer VG, Im W (2008) CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comput Chem 29:1859–1865

    Article  CAS  Google Scholar 

  28. Lee J, Cheng X, Swails JM, Yeom MS, Eastman PK, Lemkul JA, Wei S, Buckner J, Jeong JC, Yl Qi (2016) CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field. J Chem Theory Comput 12:405–413

    Article  CAS  Google Scholar 

  29. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  30. Lamoureux G, Roux B (2006) Absolute hydration free energy scale for alkali and halide ions established from simulations with a polarizable force field. J Phys Chem B 110:3308–3322

    Article  CAS  Google Scholar 

  31. Beglov D, Roux B (1994) Finite representation of an infinite bulk system: solvent boundary potential for computer simulations. J Chem Phys 100:9050–9063

    Article  CAS  Google Scholar 

  32. Hart K, Foloppe N, Baker CM, Denning EJ, Nilsson L, Mackerell AD (2012) Optimization of the CHARMM additive force field for DNA: improved treatment of the BI/BII conformational equilibrium. J Chem Theory Comput 8:348–362

    Article  CAS  Google Scholar 

  33. Mackerell AD (2004) Empirical force fields for biological macromolecules: overview and issues. J Comput Chem 25:1584–1604

    Article  CAS  Google Scholar 

  34. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kalé L, Schulten K (2005) scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802

    Article  CAS  Google Scholar 

  35. Fletcher R (ed) (2000) Practical methods of optimization: fletcher/practical methods of optimization. Wiley, Chichester

  36. Feller SE, Zhang Y, Pastor RW, Brooks BR (1995) Constant pressure molecular dynamics simulation: the Langevin piston method. J Chem Phys 103:4613–4621

    Article  CAS  Google Scholar 

  37. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  38. Laio A, Parrinello M (2002) Escaping free-energy minima. Proc Natl Acad Sci 99(99):12562–12566

    Article  CAS  Google Scholar 

  39. Tribello GA, Bonomi M, Branduardi D, Camilloni C, Bussi G (2014) PLUMED 2: new feathers for an old bird. Comput Phys Commun 185:604–613

    Article  CAS  Google Scholar 

  40. Pietrucci F (2017) Strategies for the exploration of free energy landscapes: unity in diversity and challenges ahead. Rev Phys 2:32–45

    Article  Google Scholar 

  41. Branduardi D, Gervasio FL, Parrinello M (2007) From A to B in free energy space. J Chem Phys 126:054103

    Article  Google Scholar 

  42. Crespo Y, Marinelli F, Pietrucci F, Laio A (2010) Metadynamics convergence law in a multidimensional system. Phys Rev E Stat Nonlinear Soft Matter Phys 81:055701

    Article  Google Scholar 

  43. Johansson MU, Zoete V, Michielin O, Guex N (2012) Defining and searching for structural motifs using DeepView/Swiss-PdbViewer. BMC Bioinform 13:173

    Article  Google Scholar 

  44. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612

    Article  CAS  Google Scholar 

  45. Harrisson CB, Schulten K (2012) Quantum and classical dynamics simulations of ATP hydrolysis in solution. J Chem Theory Comput 8:2328–2335

    Article  Google Scholar 

  46. de Meis L (1989) Role of water in the energy of hydrolysis of phosphate compounds—energy transduction in biological membranes. Biochem Biophys Acta 973:333–349

    PubMed  Google Scholar 

  47. George P, Witonsky RJ, Trachtman M, Wu C, Dorwart W, Richman L, Richman W, Shurayh F, Lentz B (1970) “Squiggle-H2O”. An enquiry into the importance of solvation effects in phosphate ester and anhydride reactions. Biochem Biophys Acta 223:1–15

    CAS  PubMed  Google Scholar 

  48. Vergani P, Nair AC, Gadsby D (2003) On the machanism of MgATP-dependent gating of CFTR Cl− channels. J Gen Physiol 121:17–36

    Article  CAS  Google Scholar 

  49. Fay JF, Aleksandrov LA, Jensen TJ, Cui LL, Kousouros JN, He L, Aleksandrov AA, Gingerich DS, Riordan J, Chen JZ (2018) Cryo-EM visualization of an active high open probability CFTR ion channel. bioRxiv 274316

  50. Alam A, Küng R, Kowal J, McLeod R, Tremp N, Broude E, Roninson I, Stahlberg H, Locher K (2018) Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1. Proc Natl Acad Sci USA 115:E1973–E1982

    Article  Google Scholar 

  51. Kim Y, Chen J (2018) Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science 359:915–919

    Article  CAS  Google Scholar 

  52. Johnson ZL, Chen J (2017) Structural basis of substrate recognition by the multidrug resistance protein MRP1. Cell 68:1075–1085

    Article  Google Scholar 

  53. Hohl M, Hürlimann LM, Böhm S, Schöppe J, Grütter MG, Bordignon E, Seeger MA (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

    Article  CAS  Google Scholar 

  54. Cooley RB, Arp DJ, Karplus PA (2010) Evolutionary origin of secondary structures: π-helices as cryptic but widespread insertional variations of α-helices that enhance protein functionality. J Mol Biol 404:232–246

    Article  CAS  Google Scholar 

  55. Riek RP, Graham RM (2011) The elusive π-helix. J Struct Biol 173:153–160

    Article  CAS  Google Scholar 

  56. Li M, Cowley E, El Hiani Y, Linsdell P (2018) Functional organization of cytoplasmic portals controlling access to the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel pore. J Biol Chem 293:5649–5658

    Article  CAS  Google Scholar 

  57. Barreto-Ojeda E, Corradi V, Gu RX, Tieleman DP (2018) Coarse-grained molecular dynamics simulations reveal lipid access pathways in P-glycoprotein. J Gen Physiol. https://doi.org/10.1085/jgp.201711907

    Article  PubMed  PubMed Central  Google Scholar 

  58. Dawson RJ, Locher KP (2006) Structure of a bacterial multidrug ABC transporter. Nature 443:180–185

    Article  CAS  Google Scholar 

  59. 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

    Article  CAS  Google Scholar 

  60. Katzmann D, Epping E, Moye-Rowley W (1999) Mutational disruption of plasma membrane trafficking of Saccharomyces cerevisiae Yor1p, a homologue of mammalian multidrug resistance protein. Mol Cell Biol 19:2998–3009

    Article  CAS  Google Scholar 

  61. Göddeke H, Timachi M, Hutter C, Galazzo L, Seeger M, Karttunen M, Bordignon E, Schäfer L (2018) Atomistic mechanism of large-scale conformational transition in a heterodimeric ABC exporter. J Am Chem Soc 140:4543–4551

    Article  Google Scholar 

  62. Locher KP (2016) Mechanistic diversity in ATP-binding cassette (ABC) transporters. Nat Struct Mol Biol 23:487–493

    Article  CAS  Google Scholar 

  63. Karpowich N, Martsinkevich O, Millen L, Yuan YR, Dai PL, MacVey K, Thomas PJ, Hunt JF (2001) Crystal structures of the MJ1267 ATP binding cassette reveal an induced-fit effect at the ATPase active site of an ABC transporter. Structure 9:571–586

    Article  CAS  Google Scholar 

  64. Naoe Y, Nakamura N, Doi A, Sawabe M, Nakamura H, Shiro Y, Sugimoto H (2016) Crystal structure of bacterial haem importer complex in the inward-facing conformation. Nat Commun 7:13411

    Article  CAS  Google Scholar 

  65. Woo J, Zeltina A, Goetz B, Locher K (2012) X-ray structure of the Yersinia pestis heme transporter HmuUV. Nat Struct Mol Biol 19:1310–1315

    Article  CAS  Google Scholar 

  66. Wang C, Karpowich N, Hunt J, Rance M, Palmer A (2004) Dynamics of ATP-binding cassette contribute to allosteric control, nucleotide binding and energy transduction in ABC transporters. J Mol Biol 342:525–537

    Article  CAS  Google Scholar 

  67. Li N, Wu JX, Ding D, Cheng J, Gao N, Chen L (2017) Structure of a pancreatic ATP-sensitive potassium channel. Cell 168:101–110

    Article  CAS  Google Scholar 

  68. Martin GM, Yoshioka C, Rex EA, Fay JF, Xie Q, Whorton MR, Chen JZ, Shyng SL (2017) Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating. Elife 6:e24149

    Article  Google Scholar 

  69. Thelin WR, Chen Y, Gentzsch M, Kreda SM, Sallee JL, Scarlett CO, Borchers CH, Jacobson K, Stutts MJ, Milgram SL (2007) Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Investig 117:364–374

    Article  CAS  Google Scholar 

  70. Feng Y, Walsh CA (2004) The many faces of filamin: a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol 6:1034–1038

    Article  CAS  Google Scholar 

  71. Nakamura F, Stossel TP, Hartwig JH (2011) The filamins. Cell Adhes Migr 5:160–169

    Article  Google Scholar 

  72. Playford MP, Nurminen E, Pentikäinen OT, Milgram SL, Hartwig JH, Stossel TP, Nakamura F (2010) Cystic fibrosis transmembrane conductance regulator interacts with multiple immunoglobulin domains of filamin A. J Biol Chem 285:17156–17165

    Article  CAS  Google Scholar 

  73. Smith L, Page RC, Xu Z, Kohli E, Litman P, Nix J, Ithychanda SS, Liu J, Qin J, Misra S et al (2010) Biochemical basis of the interaction between cystic fibrosis transmembrane conductance regulator and immunoglobulin-like repeats of filamin. J Biol Chem 285:17166–17176

    Article  CAS  Google Scholar 

  74. Light S, Sagit R, Ithychanda SS, Qin J, Elofsson A (2015) The evolution of filamin-a protein domain repeat perspective. J Struct Biol 179:289–298

    Article  Google Scholar 

  75. Sampson LJ, Leyland ML, Dart C (2003) Direct interaction between the actin-binding protein filamin-A and the inwardly rectifying potassium channel, Kir2.1. J Biol Chem 278:41988–41997

    Article  CAS  Google Scholar 

  76. Sethi R, Seppälä J, Tossavainen H, Ylilauri M, Ruskamo S, Pentikäinen OT, Pentikäinen U, Permi P, Ylänne J (2014) A novel structural unit in the N-terminal region of filamins. J Biol Chem 289:8588–8598

    Article  CAS  Google Scholar 

  77. Gaboriaud C, Bissery V, Benchetrit T, Mornon JP (1987) Hydrophobic cluster analysis: an efficient new way to compare and analyse amino acid sequences. FEBS Lett 224:149–155

    Article  CAS  Google Scholar 

  78. Callebaut I, Labesse G, Durand P, Poupon A, Canard L, Chomilier J, Henrissat B, Mornon J-P (1997) Deciphering protein sequence information through hydrophobic cluster analysis (HCA): current status and perspectives. Cell Mol Life Sci 53:621–645

    Article  CAS  Google Scholar 

  79. Bitard-Feildel T, Callebaut I (2017) Exploring the dark foldable proteome by considering hydrophobic amino acids topology. Sci Rep 7:41425

    Article  CAS  Google Scholar 

  80. Eudes R, Le Tuan K, Delettré J, Mornon J-P, Callebaut I (2007) A generalized analysis of hydrophobic and loop clusters within globular protein sequences. BMC Struct Biol 7:2

    Article  Google Scholar 

  81. Rebehmed J, Quintus F, Mornon J-P, Callebaut I (2016) The respective roles of polar/nonpolar binary patterns and amino acid composition in protein regular secondary structures explored exhaustively using hydrophobic cluster analysis. Proteins 84:624–638

    Article  CAS  Google Scholar 

  82. Wang W, He Z, O’Shaughnessy TJ, Rux J, Reenstra WW (2002) Domain-domain associations in cystic fibrosis transmembrane conductance regulator. Am J Physiol Cell Physiol 282:C1170–C1180

    Article  CAS  Google Scholar 

  83. Veit G, Avramescu RG, Chiang AN, Houck SA, Cai Z, Peters KW, Hong JS, Pollard HB, Guggino WB, Balch WE et al (2016) From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell 27:424–433

    Article  CAS  Google Scholar 

  84. Chang SY, Di A, Naren AP, Palfrey HC, Kirk KL, Nelson DJ (2002) Mechanisms of CFTR regulation by syntaxin 1A and PKA. J Cell Sci 115:783–791

    CAS  PubMed  Google Scholar 

  85. Cormet-Boyaka E, Di A, Chang SY, Naren AP, Tousson A, Nelson DJ, Kirk KL (2002) CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex. Proc Natl Acad Sci USA 99:12477–12482

    Article  CAS  Google Scholar 

  86. Li C, Roy K, Dandridge K, Naren AP (2004) Molecular assembly of cystic fibrosis transmembrane conductance regulator in plasma membrane. J Biol Chem 279:24673–24684

    Article  CAS  Google Scholar 

  87. Ameen N, Silvis M, Bradbury NA (2007) Endocytic trafficking of CFTR in health and disease. J Cyst Fibros 6:1–14

    Article  CAS  Google Scholar 

  88. Peters KW, Qi J, Johnson JP, Watkins SC, Frizzell RA (2001) Role of snare proteins in CFTR and ENaC trafficking. Pflugers Arch 443:S65–S69

    Article  CAS  Google Scholar 

  89. Ford RC (2016) ABC7/CFTR. In: Goerge A (ed) ABC transporters—40 years on. Springer International Publishing, New York, pp 319–340

    Chapter  Google Scholar 

  90. Naren AP, Cormet-Boyaka E, Fu J, Villain M, Blalock JE, Quick MW, Kirk KL (1999) CFTR chloride channel regulation by an interdomain interaction. Science 286:544–548

    Article  CAS  Google Scholar 

  91. Protasevich I, Yang Z, Wang C, Atwell S, Zhao X, Emtage S, Wetmore D, Hunt J, Brouillette CG (2010) Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1. Protein Sci 19:1917–1931

    Article  CAS  Google Scholar 

  92. Wang C, Protasevich I, Yang Z, Seehausen D, Skalak T, Zhao X, Atwell S, Spencer Emtage J, Wetmore DR, Brouillette CG 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

    Article  CAS  Google Scholar 

  93. He L, Aleksandrov AA, An J, Cui L, Yang Z, Brouillette CG, Riordan JR (2015) Restauration of NBD1 thermal stability is necessary and sufficient to correct DF508 CFTR folding and assembly. J Mol Biol 427:106–120

    Article  CAS  Google Scholar 

  94. Bakos E, Evers R, Szakács G, Tusnády GE, Welker E, Szabó K, de Haas M, van Deemter L, Borst P, Váradi A et al (1998) Functional multidrug resistance protein (MRP1) lacking the N-terminal transmembrane domain. J Biol Chem 273:32167–32175

    Article  CAS  Google Scholar 

  95. Furini S, Domene C (2016) Computational studies of transport in ion channels using metadynamics. Biochim Biophys Acta 1858:1733–1740

    Article  CAS  Google Scholar 

  96. Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ (1993) Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature 362:160–164

    Article  CAS  Google Scholar 

  97. Yu YC, Sohma Y, Hwang TC (2016) On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator. J Physiol 594:3227–3244

    Article  CAS  Google Scholar 

  98. Sorum B, Töröcsik B, Csanády L (2017) Asymmetry of movements in CFTR’s two ATP sites during pore opening serves their distinct functions. Elife 6:e29013

    Article  Google Scholar 

  99. Sorum B, Czégé D, Csanády L (2015) Timing of CFTR pore opening and structure of its transition state. Cell 163:724–733

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by the French Association Vaincre La Mucoviscidose (Paris). It was granted access to the HPC resources of IDRIS/CINES under the allocations 2014-077206, 2015-077206, 2016-077206, and 0020707206 made by GENCI.

Author information

Author notes

  1. Brice Hoffmann

    Present address: Iktos, Paris, France

  2. Jean-Paul Mornon and Isabelle Callebaut are co-senior authors.

  3. Brice Hoffmann and Ahmad Elbahnsi contribute equally to the work.

Authors and Affiliations

  1. Sorbonne Université, Muséum National d’Histoire Naturelle, UMR CNRS 7590, IRD, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, 75005, Paris, France

    Brice Hoffmann, Ahmad Elbahnsi, Fabio Pietrucci, Jean-Paul Mornon & Isabelle Callebaut

  2. INSERM U1078, SFR ScInBioS, Université de Bretagne Occidentale, Brest, France

    Pierre Lehn

  3. CNRS UMR5063, Université Grenoble-Alpes, Grenoble, France

    Jean-Luc Décout

Authors
  1. Brice Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmad Elbahnsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Lehn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Luc Décout
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fabio Pietrucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Paul Mornon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Isabelle Callebaut
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean-Paul Mornon.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 6175 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hoffmann, B., Elbahnsi, A., Lehn, P. et al. Combining theoretical and experimental data to decipher CFTR 3D structures and functions. Cell. Mol. Life Sci. 75, 3829–3855 (2018). https://doi.org/10.1007/s00018-018-2835-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-018-2835-7

Keywords

Search

Navigation