3SI7

The crystal structure of the NBD1 domain of the mouse CFTR protein, deltaF508 mutant

Summary for 3SI7

• Entry DOI: 10.2210/pdb3si7/pdb
• Descriptor: Cystic fibrosis transmembrane conductance regulator, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: cystic fibrosis, atp-binding domain, hydrolase
• Biological source: Mus musculus (mouse)
• Cellular location: Early endosome membrane; Multi-pass membrane protein (By similarity): P26361
• Total number of polymer chains: 4
• Total formula weight: 130441.08

Authors

Brautigam, C.A.,Caspa, E.,Thomas, P.J. (deposition date: 2011-06-17, release date: 2012-02-01, Last modification date: 2024-02-28)

Primary citation

Mendoza, J.L.,Schmidt, A.,Li, Q.,Nuvaga, E.,Barrett, T.,Bridges, R.J.,Feranchak, A.P.,Brautigam, C.A.,Thomas, P.J.
Requirements for efficient correction of DeltaF508 CFTR revealed by analyses of evolved sequences
Cell(Cambridge,Mass.), 148:164-174, 2012

PubMed Abstract: Misfolding of ΔF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR) underlies pathology in most CF patients. F508 resides in the first nucleotide-binding domain (NBD1) of CFTR near a predicted interface with the fourth intracellular loop (ICL4). Efforts to identify small molecules that restore function by correcting the folding defect have revealed an apparent efficacy ceiling. To understand the mechanistic basis of this obstacle, positions statistically coupled to 508, in evolved sequences, were identified and assessed for their impact on both NBD1 and CFTR folding. The results indicate that both NBD1 folding and interaction with ICL4 are altered by the ΔF508 mutation and that correction of either individual process is only partially effective. By contrast, combination of mutations that counteract both defects restores ΔF508 maturation and function to wild-type levels. These results provide a mechanistic rationale for the limited efficacy of extant corrector compounds and suggest approaches for identifying compounds that correct both defective steps.

PubMed: 22265409
DOI: 10.1016/j.cell.2011.11.023

Experimental method

X-RAY DIFFRACTION (2.25 Å)