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

The Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel located in the apical membrane of epithelial cells (UniProt P13569). Nucleotide-binding domain 1 (NBD1) is one of two cytosolic domains that bind and hydrolyze ATP to control the gating of the channel pore (PubMed: 28285144). The F508del mutation, the most prevalent cause of cystic fibrosis, occurs within NBD1 and results in the thermodynamic instability of the domain and defective assembly with the membrane-spanning domains (MSDs) (PubMed: 23891601). This defect leads to the recognition of the protein by the endoplasmic reticulum-associated degradation (ERAD) pathway, preventing it from reaching the cell surface (NIH: MedlinePlus). Pharmacological correctors like Elexacaftor and Tezacaftor are designed to bind to CFTR, often interacting with NBD1 or its interfaces, to stabilize the protein and promote its trafficking to the plasma membrane (PubMed: 31697873). Restoring NBD1 stability is a primary therapeutic goal to alleviate the multi-organ symptoms of cystic fibrosis, including chronic lung infections and pancreatic insufficiency.

Other names

NBD1ATP-binding cassette sub-family C member 7 nucleotide-binding domain 1ABCC7-NBD1Cystic fibrosis transmembrane conductance regulator domain 1

Pharmacological chaperone or corrector that stabilizes the NBD1 domain or its interface with other domains to improve protein folding, prevent premature degradation, and increase trafficking to the cell surface.