Cystic fibrosis transmembrane conductance regulator nucleotide-binding domain 1 (CFTR NBD1) (CFTR NBD1)

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Nucleotide-Binding Domain 1 (NBD1) is a vital regulatory component of the CFTR protein, an ATP-binding cassette (ABC) transporter that functions as a phosphorylation-activated chloride channel (UniProt: P13569). NBD1 plays a central role in channel gating by binding and hydrolyzing ATP, which facilitates the conformational changes necessary for ion transport across epithelial membranes (PubMed: 29311295). The domain is the site of the F508del mutation, the most prevalent cause of Cystic Fibrosis, which impairs the thermodynamic stability of NBD1 and disrupts its assembly with the membrane-spanning domains (MSDs) (PubMed: 23873930). This instability leads to protein misfolding and subsequent degradation by the quality control machinery in the endoplasmic reticulum. Therapeutic strategies targeting NBD1 involve small-molecule correctors, such as Elexacaftor, which act as pharmacological chaperones to stabilize the domain or its interfaces, thereby promoting the trafficking of functional CFTR to the cell surface (PubMed: 31621660). Restoring NBD1 stability is essential for alleviating the multi-organ symptoms of Cystic Fibrosis, particularly in the lungs and pancreas. Beyond its role in folding, NBD1 also interacts with the regulatory (R) domain and NBD2 to coordinate the channel opening and closing cycles (PubMed: 28445152). Consequently, NBD1 is considered a cornerstone for the development of next-generation CFTR modulators aimed at correcting the underlying protein defect in the majority of CF patients.

Other names

NBD1Nucleotide-binding fold 1CFTR-NBD1ATP-binding domain 1

Pharmacological chaperones (correctors) bind to and stabilize the NBD1 domain or its interface with membrane-spanning domains to prevent premature degradation and enhance trafficking to the plasma membrane (PubMed: 31621660, PubMed: 23873930).