Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator

Hal A. Lewis, Sean G. Buchanan, Stephen K. Burley, Kris Conners, Mark Dickey, Michael Dorwart, Richard Fowler, Xia Gao, William B. Guggino, Wayne A. Hendrickson, John F. Hunt, Margaret C. Kearins, Don Lorimer, Peter C. Maloney, Kai W. Post, Kanagalaghatta R. Rajashankar, Marc E. Rutter, J. Michael Sauder, Stephanie Shriver, Patrick H. Thibodeau & 4 others Philip J. Thomas, Marie Zhang, Xun Zhao, Spencer Emtage

Research output: Contribution to journalArticle

314 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)282-293
Number of pages12
JournalEMBO Journal
Volume23
Issue number2
DOIs
StatePublished - Jan 28 2004

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Nucleotides
Adenosine Triphosphate
Phosphorylation
Chloride Channels
ATP-Binding Cassette Transporters
Adenosine Diphosphate
Adenosine Triphosphatases
Conformations
Crystal structure
Ligands
Mutation

Keywords

  • ABC transporter
  • CFTR
  • Crystal structure
  • NBD1

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Lewis, H. A., Buchanan, S. G., Burley, S. K., Conners, K., Dickey, M., Dorwart, M., ... Emtage, S. (2004). Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO Journal, 23(2), 282-293. https://doi.org/10.1038/sj.emboj.7600040

Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. / Lewis, Hal A.; Buchanan, Sean G.; Burley, Stephen K.; Conners, Kris; Dickey, Mark; Dorwart, Michael; Fowler, Richard; Gao, Xia; Guggino, William B.; Hendrickson, Wayne A.; Hunt, John F.; Kearins, Margaret C.; Lorimer, Don; Maloney, Peter C.; Post, Kai W.; Rajashankar, Kanagalaghatta R.; Rutter, Marc E.; Sauder, J. Michael; Shriver, Stephanie; Thibodeau, Patrick H.; Thomas, Philip J.; Zhang, Marie; Zhao, Xun; Emtage, Spencer.

In: EMBO Journal, Vol. 23, No. 2, 28.01.2004, p. 282-293.

Research output: Contribution to journalArticle

Lewis, HA, Buchanan, SG, Burley, SK, Conners, K, Dickey, M, Dorwart, M, Fowler, R, Gao, X, Guggino, WB, Hendrickson, WA, Hunt, JF, Kearins, MC, Lorimer, D, Maloney, PC, Post, KW, Rajashankar, KR, Rutter, ME, Sauder, JM, Shriver, S, Thibodeau, PH, Thomas, PJ, Zhang, M, Zhao, X & Emtage, S 2004, 'Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator', EMBO Journal, vol. 23, no. 2, pp. 282-293. https://doi.org/10.1038/sj.emboj.7600040
Lewis HA, Buchanan SG, Burley SK, Conners K, Dickey M, Dorwart M et al. Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO Journal. 2004 Jan 28;23(2):282-293. https://doi.org/10.1038/sj.emboj.7600040
Lewis, Hal A. ; Buchanan, Sean G. ; Burley, Stephen K. ; Conners, Kris ; Dickey, Mark ; Dorwart, Michael ; Fowler, Richard ; Gao, Xia ; Guggino, William B. ; Hendrickson, Wayne A. ; Hunt, John F. ; Kearins, Margaret C. ; Lorimer, Don ; Maloney, Peter C. ; Post, Kai W. ; Rajashankar, Kanagalaghatta R. ; Rutter, Marc E. ; Sauder, J. Michael ; Shriver, Stephanie ; Thibodeau, Patrick H. ; Thomas, Philip J. ; Zhang, Marie ; Zhao, Xun ; Emtage, Spencer. / Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. In: EMBO Journal. 2004 ; Vol. 23, No. 2. pp. 282-293.
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