CFTR 3-D Structure Consortium

Focus

Consortium members work together to expand knowledge of the structure, the energetics, and the mechanism of CFTR function. The consortium's goals are to:

• Obtain high-quality protein reagents for full-length CFTR and CFTR structural domains
• Characterize the physicochemical properties of CFTR and CFTR structural domains
• Obtain high resolution three-dimensional structures of interactions between structural domains of CFTR
• Obtain high resolution three-dimensional structures of the full length CFTR protein
• Obtain knowledge of the binding location and energetic/folding consequences of CFTR modulators on CFTR or CFTR domains

The CFTR 3-D Structure Consortium website provides the research community access to CFTR protein structures, protein reagents, and publications to assist researchers with biophysical and structural studies.

Consortium Membership 

Suggested Reading

Structures Studies of CFTR

• Yang Z, Wang C, Zhou Q, An J, Hildebrandt E, Aleksandrov LA, Kappes JC, DeLucas LJ, Riordan JR, Urbatsch IL, Hunt JF, Brouillette CG. Membrane protein stability can be compromised by detergent interactions with the extramembranous soluble domains. Protein Sci. 2014, Jun; 23(6):769-89
• Pollock N, Cant N, Rimington T, Ford RC. Purification of the cystic fibrosis transmembrane conductance regulator protein expressed in Saccharomyces cerevisiae. J Vis Exp. 2014 May 10;(87)
• He L, Aleksandrov AA, An J, Cui L, Yang Z, Brouillette CG, Riordan JR. Restoration of NBD1 Thermal Stability Is Necessary and Sufficient to Correct ΔF508 CFTR Folding and Assembly. J Mol Biol. 2014 Jul 30. pii: S0022-2836
• Cant N, Pollock N, Ford RC. CFTR structure and cystic fibrosis.Int J Biochem Cell Biol. 2014 Jul;52:15-25.
• Hildebrandt E, Zhang Q, Cant N, Ding H, Dai Q, Peng L, Fu Y, DeLucas LJ, Ford R, Kappes JC, Urbatsch IL. A survey of detergents for the purification of stable, active human cystic fibrosis transmembrane conductance regulator (CFTR). Biochim Biophys Acta. 2014 Nov;1838(11):2825-37
• Bozoky Z, Krzeminski M, Muhandiram R, Birtley JR, Al-Zahrani A, Thomas PJ, Frizzell RA, Ford RC, Forman-Kay JD. Regulatory R region of the CFTR chloride channel is a dynamic integrator of phospho-dependent intra- and intermolecular interactions. Proc Natl Acad Sci USA. 2013 Nov 19;110(47):E4427-36
• J.E. Dawson, P. Farber and J.D. Forman-Kay. Allosteric Coupling between the Intracellular Coupling Helix 4 and Regulatory Sites of the First Nucleotide-binding Domain of CFTR. PLoS One, 2013 8(9):e74347
• Hunt JF, Wang C, Ford RC. Cystic fibrosis transmembrane conductance regulator (ABCC7) structure. Cold Spring Harb Perspect Med. 2013 Feb 1;3(2):a009514. doi: 10.1101/cshperspect.a009514. Review. 
• Hudson, R.; Chong, A.; Protasevich, I.I, Vernon, R.; Noy, E.; Bihler, H.; Li An, J.; Kalid, O.; Sela-Culang, I.; Mense, M.; Senderowitz, H.; Brouillette, C,; Forman-Kay, J.D. Conformational Changes Relevant to Channel Activity and Folding within the first Nucleotide Binding Domain of CFTR. J Biol Chem. 2012, 287, 28480-94.
• Nay, E.; Senderowitz, H. Combating cystic fibrosis: in search for CF transmembrane conductance regulator (CFTR) modulators. ChemMedChem 2011, 6, 243-51
• Kanelis V, Chong PA, Forman-Kay JD. NMR spectroscopy to study the dynamics and interactions of CFTR. Methods Mol Biol. 2011;741:377-403. doi: 10.1007/978-1-61779-117-8_25.
• Thibodeau, P.H.; Richardson III, J.M.; Wang, W.; Millen, L.; Watson, J.; Mendoza, J.; Du, K.; Fischman, S.; Senderowitz, H.; Lukacs, G.; Kirk, K.; Thomas, P.J. The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis. JBC, 2010 285, 35825-35.
• Kalid, O.; Fischman, S.; Mense, M.; Shitrit, A.; Bihler, H.; Ben-Zeev, E.; Schutz, N.; Pedemonte, N.; Thomas, P.J.; Bridges, R.J.; Wetmore, D.R.; Marantz, Y.; Senderowitz, H. Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening. J. Comput. Aided. Mol. Design, 2010, 24, 971-91. 
• Protasevich I, Yang Z, Atwell S, Zhao X, Emtage S, Wetmore D, Hunt JF, Brouillette CG. Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1. Protein Sci. 2010 Oct; 19(10)1917-31. PMID: 20687133. 
• Wang C, Protasevich I, Yang Z, Seehausen D, Skalak T, Zhao X, Atwell S, Emtage SJ. Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis. Protein Sci. 2010 Oct; 19(10):1932-47. PMID: 20687163. 
• Riordan JR. CFTR function and prospects for therapy. Annu Rev Biochem. 2008; 77:701-26. PMID 18304008 

Structures of Related ABC Transporters

• Ward AB, Szewczyk P, Grimard V, Lee CW, Martinez L, Doshi R, Caya A, Villaluz M, Pardon E, Cregger C, Swartz DJ, Falson PG, Urbatsch IL, Govaerts C, Steyaert J, Chang G. Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain. Proc Natl Acad Sci USA. 2013 Aug 13;110(33):13386-91. PMCID: 23901103

Models of CFTR

• Rahman KS, Cui G, Harvey SC, McCarty NA., Modeling the conformational changes underlying channel opening in CFTR. PLoS One. 2013 Sep 27;8(9):e74574
• Dalton J, Kalid O, Schushan M, Ben-Tal N, VillFreixa J., New model of cystic fibrosis transmembrane conductance regulator proposes active channel-like conformation.J Chem Inf Model. 2012 Jul 23;52(7):1842-53.
• Mornon JP, Lehn P, Callebaut I. Molecular models of the open and closed states of the whole human CFTR protein. Cell Mol Life Sci. 2009 Nov;66(21):3469-86.
• Huang SY, Bolser D, Liu HY, Hwang TC, Zou X. Molecular modeling of the heterodimer of human CFTR's nucleotide-binding domains using a protein-protein docking approach. J Mol Graph Model. 2009 Apr;27(7):822-8.

Resources 

• CFTR Full-length and Domain Proteins (See CFTR Protein Sourcing)
• RCSB Protein Data Bank