Cystic fibrosis transmembrane conductance regulator nucleotide-binding domain 1 (F508del mutation) (ΔF508-CFTR NBD1)

The ΔF508-CFTR NBD1 domain is a critical structural component of the Cystic Fibrosis Transmembrane Conductance Regulator protein, specifically harboring the deletion of phenylalanine at position 508. This mutation, the most prevalent cause of cystic fibrosis, leads to the misfolding and thermal instability of the NBD1 domain, which in turn prevents the CFTR protein from reaching the apical membrane of epithelial cells [3, 14]. Instead, the defective protein is recognized by the cellular quality control machinery and degraded in the endoplasmic reticulum [15, 16]. Therapeutic strategies targeting this domain involve small-molecule correctors that act as pharmacological chaperones to stabilize the NBD1 structure or its interfaces with other domains [9, 18]. By restoring the stability and trafficking of the ΔF508-CFTR protein, these drugs allow for functional chloride transport at the cell surface, significantly improving clinical outcomes such as lung function and sweat chloride levels [1, 10]. Recent advances include the development of high-affinity NBD1 stabilizers that can increase the domain's thermal stability by up to 16°C, potentially normalizing CFTR function when used in combination therapies [18].

Other names

F508del-CFTR NBD1ΔF508-NBD1Nucleotide-binding domain 1 of F508del-CFTRCFTR NBD1 (ΔF508)

Pharmacological chaperone that stabilizes the NBD1 domain or its assembly with other domains (e.g., MSD2/ICL4) to facilitate proper folding and trafficking to the plasma membrane.