ncts

The Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which belongs to the family of ATPBinding Cassette (ABC) proteins, is a phosphorylation-activated but ATP-gated anion channel. Structurally, CFTR consists of two transmembrane domains (TMDs) forming an ion channel pore, two nucleotide-binding domains (NBDs) that bind and hydrolyze ATP, and a regulatory domain that is phosphorylated by protein kinase A to allow the channel to open. CFTR functions as a chloride channel in epithelial cells, where it regulates the movement of salt and water across the cell membrane, to maintain fluid balance and mucus clearance in multiple organ systems, including lungs, pancreas, liver, and intestines. Dysfunction of CFTR can cause various diseases: Loss-of-function mutations result in cystic fibrosis (CF), a multi-organ genetic disorder; whereas hyperactivity of CFTR, usually due to bacterial toxins, leads to secretory diarrhea, a condition characterized by excessive fluid secretion in the intestines. Thus, understanding how small molecule compounds—aka CFTR modulators—affect CFTR function is crucial for the development of effective therapies for both CF, secretory diarrhea, and other CFTR-related illnesses. In this presentation, I will show how we unravel the mechanisms of action for three types of drugs or drug candidates: gating potentiators, gating inhibitors, and pore blockers. I will try to integrate biophysical and biochemical approaches to understand how these reagents modify the function of this medically important protein down to the atomic level.