title: Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator.
abstract: Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that functions as a chloride channel. Nucleotide-binding domain 1 (NBD1), one of two ABC domains in CFTR, also contains sites for the predominant CF-causing mutation and, potentially, for regulatory phosphorylation. We have determined crystal structures for mouse NBD1 in unliganded, ADP- and ATP-bound states, with and without phosphorylation. This NBD1 differs from typical ABC domains in having added regulatory segments, a foreshortened subdomain interconnection, and an unusual nucleotide conformation. Moreover, isolated NBD1 has undetectable ATPase activity and its structure is essentially the same independent of ligand state. Phe508, which is commonly deleted in CF, is exposed at a putative NBD1-transmembrane interface. Our results are consistent with a CFTR mechanism, whereby channel gating occurs through ATP binding in an NBD1-NBD2 nucleotide sandwich that forms upon displacement of NBD1 regulatory segments.
authors.affiliation: Structural GenomiX Inc., San Diego, CA, USA. hal_lewis@stromix.com
authors.forename: Hal A
authors.initials: HA
authors.lastname: Lewis
authors.forename: Sean G
authors.initials: SG
authors.lastname: Buchanan
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Burley
authors.forename: Kris
authors.initials: K
authors.lastname: Conners
authors.forename: Mark
authors.initials: M
authors.lastname: Dickey
authors.forename: Michael
authors.initials: M
authors.lastname: Dorwart
authors.forename: Richard
authors.initials: R
authors.lastname: Fowler
authors.forename: Xia
authors.initials: X
authors.lastname: Gao
authors.forename: William B
authors.initials: WB
authors.lastname: Guggino
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Hendrickson
authors.forename: John F
authors.initials: JF
authors.lastname: Hunt
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Kearins
authors.forename: Don
authors.initials: D
authors.lastname: Lorimer
authors.forename: Peter C
authors.initials: PC
authors.lastname: Maloney
authors.forename: Kai W
authors.initials: KW
authors.lastname: Post
authors.forename: Kanagalaghatta R
authors.initials: KR
authors.lastname: Rajashankar
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rutter
authors.forename: J Michael
authors.initials: JM
authors.lastname: Sauder
authors.forename: Stephanie
authors.initials: S
authors.lastname: Shriver
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Thibodeau
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thomas
authors.forename: Marie
authors.initials: M
authors.lastname: Zhang
authors.forename: Xun
authors.initials: X
authors.lastname: Zhao
authors.forename: Spencer
authors.initials: S
authors.lastname: Emtage
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate