title: Molecular models of the open and closed states of the whole human CFTR protein.
abstract: Cystic fibrosis transmembrane conductance regulator (CFTR), involved in cystic fibrosis (CF), is a chloride channel belonging to the ATP-binding cassette (ABC) superfamily. Using the experimental structure of Sav1866 as template, we previously modeled the human CFTR structure, including membrane-spanning domains (MSD) and nucleotide-binding domains (NBD), in an outward-facing conformation (open channel state). Here, we constructed a model of the CFTR inward-facing conformation (closed channel) on the basis of the recent corrected structures of MsbA and compared the structural features of those two states of the channel. Interestingly, the MSD:NBD coupling interfaces including F508 (DeltaF508 being the most common CF mutation) are mainly left unchanged. This prediction, completed by the modeling of the regulatory R domain, is supported by experimental data and provides a molecular basis for a better understanding of the functioning of CFTR, especially of the structural features that make CFTR the unique channel among the ABC transporters.
authors.affiliation: IMPMC, UMR7590, CNRS, Universités Pierre et Marie Curie-Paris 6 et Denis Diderot-Paris 7, 140 Rue de Lourmel, Paris, France. jean-paul.mornon@impmc.jussieu.fr
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mornon
authors.forename: Pierre
authors.initials: P
authors.lastname: Lehn
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry; D000595:Amino Acid Sequence; D003198:Computer Simulation; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D018528:ATP-Binding Cassette Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
references.citation: J Biol Chem. 2005 Jan 14;280(2):1346-53
references.pmid: 15528182
references.citation: Cell Mol Life Sci. 2004 Jan;61(2):230-42
references.pmid: 14745501
references.citation: Cell. 1990 Nov 16;63(4):827-34
references.pmid: 1699669
references.citation: Nat Struct Mol Biol. 2005 Jan;12(1):17-25
references.pmid: 15619635
references.citation: Science. 1991 Jul 12;253(5016):202-5
references.pmid: 1712984
references.citation: J Biol Chem. 2008 Oct 17;283(42):28190-7
references.pmid: 18708637
references.citation: Science. 2009 Mar 27;323(5922):1718-22
references.pmid: 19325113
references.citation: Cell Mol Life Sci. 2009 Oct;66(19):3111-26
references.pmid: 19544044
references.citation: Nature. 2006 Mar 23;440(7083):477-83
references.pmid: 16554808
references.citation: Biochemistry. 1999 Apr 27;38(17):5528-37
references.pmid: 10220340
references.citation: J Physiol. 1998 Oct 1;512 ( Pt 1):1-16
references.pmid: 9729613
references.citation: J Mol Biol. 2007 Jan 26;365(4):981-94
references.pmid: 17113596
references.citation: Science. 1989 Sep 8;245(4922):1066-73
references.pmid: 2475911
references.citation: Biochem Soc Trans. 2005 Nov;33(Pt 5):996-9
references.pmid: 16246030
references.citation: Cell. 1986 Nov 7;47(3):371-80
references.pmid: 3768958
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3256-61
references.pmid: 18305154
references.citation: Am J Hum Genet. 1999 Jun;64(6):1499-504
references.pmid: 10330337
references.citation: J Physiol. 2003 Jun 1;549(Pt 2):387-97
references.pmid: 12679372
references.citation: FEBS Lett. 2007 Mar 6;581(5):935-8
references.pmid: 17303126
references.citation: EMBO J. 2004 Jan 28;23(2):282-93
references.pmid: 14685259
references.citation: Annu Rev Biophys Biomol Struct. 2000;29:291-325
references.pmid: 10940251
references.citation: Mol Pharmacol. 2007 May;71(5):1360-8
references.pmid: 17293558
references.citation: EMBO J. 2000 Nov 15;19(22):5951-61
references.pmid: 11080142
references.citation: Electrophoresis. 1997 Dec;18(15):2714-23
references.pmid: 9504803
references.citation: Science. 1991 Jul 12;253(5016):205-7
references.pmid: 1712985
references.citation: Adv Protein Chem. 2000;54:245-75
references.pmid: 10829230
references.citation: Biochim Biophys Acta. 2009 Jun;1788(6):1341-9
references.pmid: 19328185
references.citation: BMC Struct Biol. 2007 Jan 08;7:2
references.pmid: 17210072
references.citation: EMBO J. 2006 Jan 11;25(1):24-33
references.pmid: 16341087
references.citation: Cell Mol Life Sci. 2005 Sep;62(18):2112-23
references.pmid: 16132229
references.citation: Trends Neurosci. 2004 Jun;27(6):298-302
references.pmid: 15165732
references.citation: J Gen Physiol. 2006 Oct;128(4):413-22
references.pmid: 16966475
references.citation: J Biol Chem. 2008 Oct 31;283(44):30300-10
references.pmid: 18723516
references.citation: Bioinformatics. 1999 Apr;15(4):305-8
references.pmid: 10320398
references.citation: J Biol Chem. 1996 Jun 21;271(25):15139-45
references.pmid: 8662892
references.citation: Mol Cell. 2003 Sep;12(3):651-61
references.pmid: 14527411
references.citation: Nat Rev Mol Cell Biol. 2009 Mar;10(3):218-27
references.pmid: 19234479
references.citation: Nat Rev Mol Cell Biol. 2009 May;10(5):344-52
references.pmid: 19339978
references.citation: Cell Mol Life Sci. 2008 Aug;65(16):2594-612
references.pmid: 18597042
references.citation: J Struct Biol. 2009 Sep;167(3):242-51
references.pmid: 19524678
references.citation: Neuron. 1994 Sep;13(3):623-34
references.pmid: 7522483
references.citation: Science. 2003 Apr 4;300(5616):108-12
references.pmid: 12649487
references.citation: Curr Opin Struct Biol. 2007 Aug;17(4):412-8
references.pmid: 17723295
references.citation: J Gen Physiol. 2006 Nov;128(5):535-45
references.pmid: 17043152
references.citation: J Biol Chem. 2004 Dec 31;279(53):55283-9
references.pmid: 15504721
references.citation: N Engl J Med. 2005 May 12;352(19):1992-2001
references.pmid: 15888700
references.citation: Hum Mutat. 2008 Nov;29(11):1364-72
references.pmid: 18951463
references.citation: Curr Opin Struct Biol. 2008 Dec;18(6):726-33
references.pmid: 18948194
references.citation: FEBS Lett. 1987 Nov 16;224(1):149-55
references.pmid: 3678489
references.citation: J Biol Chem. 2004 Sep 10;279(37):39051-7
references.pmid: 15247233
references.citation: EMBO J. 2005 Aug 3;24(15):2730-40
references.pmid: 16001079
references.citation: J Mol Biol. 2003 Jul 4;330(2):343-58
references.pmid: 12823973
references.citation: Pflugers Arch. 2008 Nov;457(2):351-60
references.pmid: 18449561
references.citation: J Biol Chem. 2001 Mar 16;276(11):7689-92
references.pmid: 11244086
references.citation: FEBS Lett. 2006 Feb 13;580(4):1023-35
references.pmid: 16375896
references.citation: J Mol Biol. 2008 May 16;378(5):1052-63
references.pmid: 18423665
references.citation: Science. 1999 Oct 15;286(5439):544-8
references.pmid: 10521352
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19005-10
references.pmid: 18024585
references.citation: Biochemistry. 2002 Nov 5;41(44):13170-7
references.pmid: 12403618
references.citation: Cell Mol Life Sci. 1997 Aug;53(8):621-45
references.pmid: 9351466
references.citation: J Membr Biol. 2009 Apr;228(3):151-64
references.pmid: 19381710
references.citation: Cell. 1992 Feb 21;68(4):809-18
references.pmid: 1371239
references.citation: Cell. 1995 Oct 6;83(1):121-7
references.pmid: 7553863
references.citation: Nat Struct Mol Biol. 2007 Aug;14(8):738-45
references.pmid: 17660831
references.citation: Cell. 1991 Sep 6;66(5):1027-36
references.pmid: 1716180
references.citation: J Biol Chem. 2001 Sep 21;276(38):35660-8
references.pmid: 11468285