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Structure basis of CFTR folding, function and pharmacology

  • Author Footnotes
    1 These authors contribute equally and should be considered as co-first authors.
    Tzyh-Chang Hwang
    Footnotes
    1 These authors contribute equally and should be considered as co-first authors.
    Affiliations
    Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taiwan

    Department of Medical Pharmacology and Physiology, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA
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  • Author Footnotes
    1 These authors contribute equally and should be considered as co-first authors.
    Ineke Braakman
    Footnotes
    1 These authors contribute equally and should be considered as co-first authors.
    Affiliations
    Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands
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  • Peter van der Sluijs
    Affiliations
    Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands
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  • Isabelle Callebaut
    Correspondence
    Corresponding author at: Sorbonne Université, Muséum National d'Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, 75005 Paris, France.
    Affiliations
    Sorbonne Université, Muséum National d'Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, 75005 Paris, France
    Search for articles by this author
  • Author Footnotes
    1 These authors contribute equally and should be considered as co-first authors.
Published:October 07, 2022DOI:https://doi.org/10.1016/j.jcf.2022.09.010

      Abstract

      The root cause of cystic fibrosis (CF), the most common life-shortening genetic disease in the Caucasian population, is the loss of function of the CFTR protein, which serves as a phosphorylation-activated, ATP-gated anion channel in numerous epithelia-lining tissues. In the past decade, high-throughput drug screening has made a significant stride in developing highly effective CFTR modulators for the treatment of CF. Meanwhile, structural-biology studies have succeeded in solving the high-resolution three-dimensional (3D) structure of CFTR in different conformations. Here, we provide a brief overview of some striking features of CFTR folding, function and pharmacology, in light of its specific structural features within the ABC-transporter superfamily. A particular focus is given to CFTR's first nucleotide-binding domain (NBD1), because folding of NBD1 constitutes a bottleneck in the CFTR protein biogenesis pathway, and ATP binding to this domain plays a unique role in the functional stability of CFTR. Unraveling the molecular basis of CFTR folding, function, and pharmacology would inspire the development of next-generation mutation-specific CFTR modulators.

      Keywords

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      References

        • Csanády L.
        • Vergani P.
        • Gadsby D.C.
        Structure, gating, and regulation of the CFTR anion channel.
        Physiol Rev. 2019; 99: 707-738
        • Hwang T.C.
        • Sheppard D.N.
        Gating of the CFTR Cl- channel by ATP-driven nucleotide-binding domain dimerisation.
        J Physiol. 2009; 587: 2151-2161
        • Hwang T.C.
        • Yeh J.T.
        • Zhang J.
        • Yu Y.C.
        • Yeh H.I.
        • Destefano S.
        Structural mechanisms of CFTR function and dysfunction.
        J Gen Physiol. 2018; 150: 539-570
        • Infield D.T.
        • Strickland K.M.
        • Gaggar A.
        • McCarty N.A.
        The molecular evolution of function in the CFTR chloride channel.
        J Gen Physiol. 2021; 153e202012625
        • Bai Y.
        • Li M.
        • Hwang T.C.
        Structural basis for the channel function of a degraded ABC transporter, CFTR (ABCC7).
        J Gen Physiol. 2011; 138: 495-507
        • Liu F.
        • Zhang Z.
        • Csanády L.
        • Gadsby D.C.
        • Chen J.
        Molecular structure of the human CFTR ion channel.
        Cell. 2017; 169: 85-95
        • Mornon J.-.P.
        • Hoffmann B.
        • Jonic S.
        • Lehn P.
        • Callebaut I.
        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. 2015; 72: 1377-1403
        • Zhang Z.
        • Liu F.
        • Chen J.
        Molecular structure of the ATP-bound, phosphorylated human CFTR.
        Proc Natl Acad Sci USA. 2018; 115: 12757-12762
        • Aleksandrov A.A.
        • Kota P.
        • Aleksandrov L.A.
        • He L.
        • Jensen T.
        • Cui L.
        • et al.
        Regulatory insertion removal restores maturation, stability and function of DeltaF508 CFTR.
        J Mol Biol. 2010; 401: 194-210
        • Csanády L.
        • Chan K.W.
        • Nairn A.C.
        • Gadsby D.C.
        Functional roles of nonconserved structural segments in CFTR's NH2-terminal nucleotide binding domain.
        J Gen Physiol. 2005; 125: 43-55
        • Negoda A.
        • Hogan M.S.
        • Cowley E.A.
        Linsdell P. Contribution of the eighth transmembrane segment to the function of the CFTR chloride channel pore.
        Cell Mol Life Sci. 2019; 76: 2411-2423
        • Li M.
        • Cowley E.
        • El Hiani Y.
        • Linsdell P
        Functional organization of cytoplasmic portals controlling access to the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel pore.
        J Biol Chem. 2018; 293: 5649-5658
        • Hoffmann B.
        • Elbahnsi A.
        • Lehn P.
        • Décout J.-.L.
        • Pietrucci F.
        • Mornon J.-.P.
        • et al.
        Combining theoretical and experimental data to decipher CFTR 3D structures and functions.
        Cell Mol Life Sci. 2018; 75: 3829-3855
        • Naren A.P.
        • Cormet-Boyaka E.
        • Fu J.
        • Villain M.
        • Blalock J.E.
        • Quick M.W.
        • et al.
        CFTR chloride channel regulation by an interdomain interaction.
        Science. 1999; 286: 544-548
        • Liu F.
        • Zhang Z.
        • Levit A.
        • Levring J.
        • Touhara K.K.
        • Shoichet B.K.
        • et al.
        Structural identification of a hotspot on CFTR for potentiation.
        Science. 2019; 364: 1184-1188
        • Fiedorczuk K.
        • Chen J.
        Mechanism of CFTR correction by type I folding correctors.
        Cell. 2022; 185: 158-168
        • Baatallah N.
        • Elbahnsi A.
        • Mornon J.-.P.
        • Chevalier B.
        • Pranke I.
        • Servel N.
        • et al.
        Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR.
        Cell Mol Life Sci. 2021; 78: 7813-7829
        • Anglès F.
        • Wang C.
        • Balch W.E.
        Spatial covariance analysis reveals the residue-by-residue thermodynamic contribution of variation to the CFTR fold.
        Commun Biol. 2022; 5: 356
        • Wang C.
        • Balch W.E.
        Bridging genomics to phenomics at atomic resolution through variation spatial profiling.
        Cell Rep. 2018; 24 (e6): 2013-2028
        • Kim S.J.
        • Skach W.R.
        Mechanisms of CFTR folding at the endoplasmic reticulum.
        Front Pharmacol. 2012; 3: 201
        • Kleizen B.
        • van Vlijmen T.
        • de Jonge H.R.
        • Braakman I.
        Folding of CFTR is predominantly cotranslational.
        Mol Cell. 2005; 20: 277-287
        • Kleizen B.
        • van Willigen M.
        • Mijnders M.
        • Peters F.
        • Grudniewska M.
        • Hillenaar T.
        • et al.
        Co-translational folding of the first transmembrane domain of ABC-Transporter CFTR is supported by assembly with the first cytosolic domain.
        J Mol Biol. 2021; 433166955
      1. Im J., Hillenaar T., Yeoh H.Y., Sahasrabudhe P., Mijnders M., van Willigen M., et al. ABC-transporter CFTR folds with high fidelity through a modular, stepwise pathway. bioRxiv. 2022:2022.07.20.500765.

        • Cui L.
        • Aleksandrov L.
        • Chang X.B.
        • Hou Y.X.
        • He L.
        • Hegedus T.
        • et al.
        Domain interdependence in the biosynthetic assembly of CFTR.
        J Mol Biol. 2007; 365: 981-994
        • Hutt D.M.
        • Loguercio S.
        • Campos A.R.
        • Balch W.E.
        A proteomic variant approach (ProVarA) for personalized medicine of inherited and somatic disease.
        J Mol Biol. 2018; 430: 2951-2973
        • McDonald E.F.
        • Sabusap C.M.P.
        • Kim M.
        • Plate L
        Distinct proteostasis states drive pharmacologic chaperone susceptibility for cystic fibrosis transmembrane conductance regulator misfolding mutants.
        Mol Biol Cell. 2022; 33: ar62
        • Pankow S.
        • Bamberger C.
        • Calzolari D.
        • Martínez-Bartolomé S.
        • Lavallée-Adam M.
        • Balch W.E.
        • et al.
        ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.
        Nature. 2015; 528: 510-516
        • He L.
        • Kennedy A.S.
        • Houck S.
        • Aleksandrov A.
        • Quinney N.L.
        • Cyr-Scully A.
        • et al.
        DNAJB12 and Hsp70 triage arrested intermediates of N1303K-CFTR for endoplasmic reticulum-associated autophagy.
        Mol Biol Cell. 2021; 32: 538-553
        • Liu Q.
        • Sabirzhanova I.
        • Yanda M.K.
        • Bergbower E.A.S.
        • Boinot C.
        • Guggino W.B.
        • et al.
        Rescue of CFTR NBD2 mutants N1303K and S1235R is influenced by the functioning of the autophagosome.
        J Cyst Fibros. 2018; 17: 582-594
        • van Willigen M.
        • Vonk A.M.
        • Yeoh H.Y.
        • Kruisselbrink E.
        • Kleizen B.
        • van der Ent C.K.
        • et al.
        Folding-function relationship of the most common cystic fibrosis-causing CFTR conductance mutants.
        Life Sci Alliance. 2019; 2e201800172
        • Veit G.
        • Avramescu R.G.
        • Chiang A.N.
        • Houck S.A.
        • Cai Z.
        • Peters K.W.
        • et al.
        From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.
        Mol Biol Cell. 2016; 27: 424-433
        • Santos J.D.
        • Canato S.
        • Carvalho A.S.
        • Botelho H.M.
        • Aloria K.
        • Amaral M.D.
        • et al.
        Folding status is determinant over traffic-competence in defining CFTR interactors in the endoplasmic reticulum.
        Cells. 2019; 8: E353
        • Mendoza J.L.
        • Schmidt A.
        • Li Q.
        • Nuvaga E.
        • Barrett T.
        • Bridges R.J.
        • et al.
        Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences.
        Cell. 2012; 148: 164-174
        • Rabeh W.M.
        • Bossard F.
        • Xu H.
        • Okiyoneda T.
        • Bagdany M.
        • Mulvihill C.M.
        • et al.
        Correction of both NBD1 energetics and domain interface is required to restore ΔF508 CFTR folding and function.
        Cell. 2012; 148: 150-163
        • Thibodeau P.H.
        • JMr Richardson
        • Wang W.
        • Millen L.
        • Watson J.
        • Mendoza J.L.
        • et al.
        The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis.
        J Biol Chem. 2010; 285: 35825-35835
        • Protasevich I.
        • Yang Z.
        • Wang C.
        • Atwell S.
        • Zhao X.
        • Emtage S.
        • et al.
        Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1.
        Protein Sci. 2010; 19: 1917-1931
        • Wang C.
        • Protasevich I.
        • Yang Z.
        • Seehausen D.
        • Skalak T.
        • Zhao X.
        • et al.
        Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis.
        Protein Sci. 2010; 19: 1932-1947
        • Qu B.H.
        • Strickland E.H.
        • Thomas P.J.
        Localization and suppression of a kinetic defect in cystic fibrosis transmembrane conductance regulator folding.
        J Biol Chem. 1997; 272: 15739-15744
        • Khushoo A.
        • Yang Z.
        • Johnson A.E.
        • Skach W.R.
        Ligand-driven vectorial folding of ribosome-bound human CFTR NBD1.
        Mol Cell. 2011; 41: 682-692
        • Scholl D.
        • Sigoillot M.
        • Overtus M.
        • Martinez R.C.
        • Martens C.
        • Wang Y.
        • et al.
        A topological switch in CFTR modulates channel activity and sensitivity to unfolding.
        Nat Chem Biol. 2021; 17: 989-997
      2. Hillenaar T., Beekman J., van der Sluijs P., Braakman I. Redefining hypo- and hyper-responding phenotypes of CFTR mutants for understanding and therapy. bioRxiv. 2022:2022.09.12.507537.

        • Capurro V.
        • Tomati V.
        • Sondo E.
        • Renda M.
        • Borrelli A.
        • Pastorino C.
        • et al.
        Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment.
        Int J Mol Sci. 2021; 22: 5262
        • Okiyoneda T.
        • Veit G.
        • Dekkers J.F.
        • Bagdany M.
        • Soya N.
        • Xu H.
        • et al.
        Mechanism-based corrector combination restores ΔF508-CFTR folding and function.
        Nat Chem Biol. 2013; 9: 444-454
        • Sabusap C.M.
        • Joshi D.
        • Simhaev L.
        • Oliver K.E.
        • Senderowitz H.
        • van Willigen M.
        • et al.
        The CFTR P67L variant reveals a key role for N-terminal lasso helices in channel folding, maturation, and pharmacologic rescue.
        J Biol Chem. 2021; 296100598
        • Van Goor F.
        • Hadida S.
        • Grootenhuis P.D.
        • Burton B.
        • Stack J.H.
        • Straley K.S.
        • et al.
        Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809.
        Proc Natl Acad Sci U S A. 2011; 108: 18843-18848
        • Veit G.
        • Roldan A.
        • Hancock M.A.
        • Da Fonte D.F.
        • Xu H.
        • Hussein M.
        • et al.
        Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination.
        JCI Insight. 2020; 5e139983
        • Singh A.K.
        • Fan Y.
        • Balut C.
        • Alani S.
        • Manelli A.M.
        • Swensen A.M.
        • et al.
        Biological characterization of F508delCFTR protein processing by the CFTR corrector ABBV-2222/GLPG2222.
        J Pharmacol Exp Ther. 2020; 372: 107-118
        • Van Goor F.
        • Hadida S.
        • Grootenhuis P.D.
        • Burton B.
        • Cao D.
        • Neuberger T.
        • et al.
        Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770.
        Proc Natl Acad Sci U S A. 2009; 106: 18825-18830
        • Wang C.
        • Aleksandrov A.A.
        • Yang Z.
        • Forouhar F.
        • Proctor E.A.
        • Kota P.
        • et al.
        Ligand binding to a remote site thermodynamically corrects the F508del mutation in the human cystic fibrosis transmembrane conductance regulator.
        J Biol Chem. 2018; 293: 17685-17704
        • Ren H.Y.
        • Grove D.E.
        • Houck S.A.
        • Sopha P.
        • van Goor F.
        • Hoffman B.J.
        • et al.
        VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1.
        Mol Biol Cell. 2013; 24: 3016-3024
        • Patrick A.E.
        • Karamyshev A.L.
        • Millen L.
        • Thomas P.J.
        Alteration of CFTR transmembrane span integration by disease-causing mutations.
        Mol Biol Cell. 2011; 22: 4461-4471
        • Xiong X.
        • Bragin A.
        • Widdicombe J.H.
        • Cohn J.
        • Skach W.R.
        Structural cues involved in endoplasmic reticulum degradation of G85E and G91R mutant cystic fibrosis transmembrane conductance regulator.
        J Clin Invest. 1997; 100: 1079-1088
        • Oliver K.E.
        • Rauscher R.
        • Mijnders M.
        • Wang W.
        • Wolpert M.J.
        • J M.
        • et al.
        Slowing ribosome velocity restores folding and function of mutant CFTR.
        J Clin Invest. 2019; 129: 5236-5253
        • Hudson R.P.
        • Chong P.A.
        • Protasevich I.I.
        • Vernon R.
        • Noy E.
        • Bihler H.
        • et al.
        Conformational changes relevant to channel activity and folding within the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator.
        J Biol Chem. 2012; 287: 28480-28494
        • Laselva O.
        • Bartlett C.
        • Gunawardena T.N.A.
        • Ouyang H.
        • Eckford P.D.W.
        • Moraes T.J.
        • et al.
        Rescue of multiple class II CFTR mutations by elexacaftor+tezacaftor+ivacaftor mediated in part by the dual activities of elexacaftor as both corrector and potentiator.
        Eur Respir J. 2021; 572002774
        • Shaughnessy C.A.
        • Zeitlin P.L.
        • Bratcher P.E.
        Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment.
        Sci Rep. 2021; 11: 19810
        • Veit G.
        • Vaccarin C.
        • Lukacs G.L.
        Elexacaftor co-potentiates the activity of F508del and gating mutants of CFTR.
        J Cyst Fibros. 2021; 20: 895-898
        • Abu-Arish A.
        • Pandzic E.
        • Goepp J.
        • Matthes E.
        • Hanrahan J.W.
        • Wiseman P.W.
        Cholesterol modulates CFTR confinement in the plasma membrane of primary epithelial cells.
        Biophys J. 2015; 109: 85-94
        • Abu-Arish A.
        • Pandžić E.
        • Luo Y.
        • Sato Y.
        • Turner M.J.
        • Wiseman P.W.
        • et al.
        Lipid-driven CFTR clustering is impaired in CF and restored by corrector drugs.
        J Cell Sci. 2022; 135jcs259002
        • Cottrill K.A.
        • Farinha C.M.
        • McCarty N.A.
        The bidirectional relationship between CFTR and lipids.
        Commun Biol. 2020; 3: 179
        • Billet A.
        • Elbahnsi A.
        • Jollivet-Souchet M.
        • Hoffmann B.
        • Mornon J.P.
        • Callebaut I.
        • et al.
        Functional and pharmacological characterization of the rare CFTR mutation W361R.
        Front Pharmacol. 2020; 17: 295
        • Cheng S.H.
        • Rich D.P.
        • Marshall J.
        • Gregory R.J.
        • Welsh M.J.
        • Smith A.E.
        Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel.
        Cell. 1991; 66: 1027-1036
        • Picciotto M.R.
        • Cohn J.A.
        • Bertuzzi G.
        • Greengard P.
        • Nairn A.C.
        Phosphorylation of the cystic fibrosis transmembrane conductance regulator.
        J Biol Chem. 1992; 267: 12742-12752
        • Mihályi C.
        • Iordanov I.
        • Töröcsik B.
        • Csanády L.
        Simple binding of protein kinase A prior to phosphorylation allows CFTR anion channels to be opened by nucleotides.
        Proc Natl Acad Sci U S A. 2020; 117: 21740-21746
        • Zhang Z.
        • Liu F.
        • Chen J.
        Conformational changes of CFTR upon phosphorylation and ATP binding.
        Cell. 2017; 170: 483-491
        • Vergani P.
        • Lockless S.W.
        • Nairn A.C.
        • Gadsby D.C.
        CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains.
        Nature. 2005; 433: 876-880
        • Vergani P.
        • Nair A.C.
        • Gadsby D.
        On the mechanism of MgATP-dependent gating of CFTR Cl channels.
        J Gen Physiol. 2003; 121: 17-36
        • Bompadre S.G.
        • Cho J.H.
        • Wang X.
        • Zou X.
        • Sohma Y.
        • Li M.
        • et al.
        CFTR gating II: effects of nucleotide binding on the stability of open states.
        J Gen Physiol. 2005; 125: 377-394
        • Gadsby D.C.
        • Vergani P.
        • Csanády L.
        The ABC protein turned chloride channel whose failure causes cystic fibrosis.
        Nature. 2006; 440: 477-483
        • Chen T.Y.
        • Hwang T.C.
        CLC-0 and CFTR: chloride channels evolved from transporters.
        Physiol Rev. 2008; 88: 351-387
        • Sohma Y.
        • Hwang T.C.
        Cystic fibrosis and the CFTR anion channel.
        (editor)in: Zheng J. Trudeau M.C. Handbook of ion channels. CRC Press, Boca Raton, FL2015: 627-648
        • Csanády L.
        • Vergani P.
        • Gadsby D.C.
        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 U S A. 2010; 107: 1241-1246
        • Jih K.Y.
        • Sohma Y.
        • Hwang T.C.
        Nonintegral stoichiometry in CFTR gating revealed by a pore-lining mutation.
        J Gen Physiol. 2012; 140: 347-359
        • Lin W.-.Y.
        • Jih K.-.Y.
        • Hwang T.C.
        A single amino acid substitution in CFTR converts ATP to an inhibitory ligand.
        J Gen Physiol. 2014; 144: 311-320
        • Lin W.-.Y.
        • Shoma Y.
        • Hwang T.C.
        Synergistic potentiation of cystic fibrosis transmembrane conductance regulator gating by two chemically distinct potentiators, ivacaftor (VX-770) and 5-Nitro-2-(3-Phenylpropylamino) Benzoate.
        Mol Pharmac. 2016; 90: 275-286
        • Aleksandrov A.A.
        • Cui L.
        • Riordan J.R
        Relationship between nucleotide binding and ion channel gating in cystic fibrosis transmembrane conductance regulator.
        J Physiol. 2009; 587: 2875-2886
        • Csanády L.
        Application of rate-equilibrium free energy relationship analysis to nonequilibrium ion channel gating mechanisms.
        J Gen Physiol. 2009; 134: 129-136
        • Aleksandrov L.
        • Aleksandrov A.A.
        • Chang X.B.
        • Riordan J.R.
        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. 2002; 277: 15419-15425
        • 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. 2003; 122: 333-348
        • Tsai M.F.
        • Li M.
        • Hwang T.C.
        Stable ATP binding mediated by a partial NBD dimer of the CFTR chloride channel.
        J Gen Physiol. 2010; 135: 399-414
        • Aleksandrov L.A.
        • Fay J.F.
        • Riordan J.R.
        R-domain phosphorylation by protein kinase A stimulates dissociation of unhydrolyzed ATP from the first nucleotide-binding site of the cystic fibrosis transmembrane conductance regulator.
        Biochemistry. 2018; 57: 5073-5075
        • Jih K.Y.
        • Hwang T.C.
        Nonequilibrium gating of CFTR on an equilibrium theme.
        Physiology. 2012; 27: 351-361
        • Powe Jr., A.C.
        • Al-Nakkash L.
        • Li M.
        • Hwang T.C
        Mutation of Walker-A lysine 464 in cystic fibrosis transmembrane conductance regulator reveals functional interaction between its nucleotide-binding domains.
        J Physiol. 2002; 539: 333-346
        • Zhou Z.
        • Wang X.
        • Liu H.Y.
        • Zou X.
        • Li M.
        • Hwang T.C.
        The two ATP binding sites of cystic fibrosis transmembrane conductance regulator (CFTR) play distinct roles in gating kinetics and energetics.
        J Gen Physiol. 2006; 128: 413-422
        • Yeh H.I.
        • Yu Y.C.
        • Kuo P.L.
        • Tsai C.K.
        • Huang H.T.
        • Hwang T.C.
        Functional stability of CFTR depends on tight binding of ATP at its degenerate ATP-binding site.
        J Physiol. 2021; 599: 4625-4642
        • Jih K.Y.
        • Li M.
        • Hwang T.C.
        • Bompadre S.G.
        The most common cystic fibrosis-associated mutation destabilizes the dimeric state of the nucleotide-binding domains of CFTR.
        J Physiol. 2011; 589: 2719-2731
        • Miki H.
        • Zhou Z.
        • Li M.
        • Hwang T.C.
        • Bompadre S.G.
        Potentiation of disease-associated cystic fibrosis transmembrane conductance regulator mutants by hydrolyzable ATP analogs.
        J Biol Chem. 2010; 285: 19967-19975
        • Barry P.J.
        • Mall M.A.
        • Polineni D.
        Triple therapy for cystic fibrosis Phe508del-gating and -residual function genotypes. Reply.
        N Engl J Med. 2021; 385: 815-825
        • Middleton P.G.
        • Mall M.A.
        • Dřevínek P.
        • Lands L.C.
        • McKone E.F.
        • Polinemi D.
        • et al.
        Elexacaftor–Tezacaftor–Ivacaftor for cystic fibrosis with a single Phe508del allele.
        N Engl J Med. 2019; 381: 1809-1819
        • Yeh H.I.
        • Sutcliffe K.J.
        • Sheppard D.N.
        • Hwang T.C.
        CFTR Modulators: from mechanism to targeted therapeutics.
        Handb Exp Pharmacol. 2022; (Aug 17 Online ahead of print)https://doi.org/10.1007/164_2022_597
        • Accurso F.J.
        • Rowe S.M.
        • Clancy J.P.
        • Boyle M.P.
        • Dunitz J.M.
        • Durie P.R.
        • et al.
        Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.
        N Engl J Med. 2010; 363: 1991-2003
        • Ramsey B.W.
        • Davies J.
        • McElvaney N.G.
        • Tullis E.
        • Bell S.C.
        • Dřevínek P.
        • et al.
        A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
        N Engl J Med. 2011; 365: 1663-1672
        • Eckford P.D.
        • Li C.
        • Ramjeesingh M.
        • Bear C.E.
        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. 2012; 287: 36639-36649
        • Jih K.Y.
        • Hwang T.C.
        Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle.
        Proc Natl Acad Sci U S A. 2013; 110: 4404-4409
        • Yeh H.I.
        • Yeh J.T.
        • Hwang T.C.
        Modulation of CFTR gating by permeant ions.
        J Gen Physiol. 2015; 145: 47-60
        • Yeh H.
        • Sohma Y.
        • Conrath K.
        • Hwang T.C.
        A common mechanism for CFTR potentiators.
        J Gen Physiol. 2017; 149: 1105-1118
        • Yeh H.-.I.
        • Qiu L.
        • Sohma Y.
        • Conrath K.
        • Zou X.
        • Hwang T.C.
        Identifying the molecular target sites for CFTR potentiators GLPG1837 and VX-770.
        J Gen Physiol. 2019; 151: 912-928
        • Bose S.J.
        • Krainer G.
        • Ng D.R.
        • Schenkel M.
        • Shishido H.
        • Yoon J.S.
        • et al.
        Towards next generation therapies for cystic fibrosis: folding, function and pharmacology of CFTR.
        J Cyst Fibros. 2019;
        • Laselva O.
        • Qureshi Z.
        • Zeng Z.W.
        • Petrotchenko E.V.
        • Ramjeesingh M.
        • Hamilton C.M.
        • et al.
        Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator.
        iScience. 2021; 24102542
        • Corradi V.
        • Gu R.-.X.
        • Vergani P.
        • Tieleman D.
        Structure of transmembrane helix 8 and possible membrane defects in CFTR.
        Biophys J. 2018; 114: 1751-1754
        • Van Goor F.
        • Yu H.
        • Burton B.
        • Hoffman B
        Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function.
        J Cyst Fibros. 2014; 13: 29-36
        • Cotten J.F.
        • Welsh M.J.
        Cystic fibrosis-associated mutations at arginine 347 alter the pore architecture of CFTR. Evidence for disruption of a salt bridge.
        J Biol Chem. 1999; 274: 5429-5435
        • Sheppard D.N.
        • Rich D.P.
        • Ostedgaard L.S.
        • Gregory R.J.
        • Smith A.E.
        • Welsh M.J.
        Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties.
        Nature. 1993; 362: 160-164
        • Yu Y.C.
        • Sohma Y.
        • Hwang T.C.
        On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator.
        J Physiol. 2016; 594: 3227-3244
        • Simon M.A.
        • Csanády L.M.
        Molecular pathology of the R117H cystic fibrosis mutation is explained by loss of a hydrogen bond.
        Elife. 2021; 10: e74693
        • Wong S.L.
        • Awatade N.T.
        • Astore M.A.
        • Allan K.M.
        • Carnell M.J.
        • Slapetova I.
        • et al.
        Molecular dynamics and functional characterization of I37R-CFTR lasso mutation provide insights into channel gating activity.
        iScience. 2021; 25103710