Decoding CFTR: Unveiling the Protein’s Role in Cystic Fibrosis and Diarrheal Diseases
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is essential for regulating chloride ion (a type of electrolyte) transport and maintaining proper hydration across cell membranes, which is crucial for the respiratory and digestive systems. Mutations in CFTR disrupt these pathways, leading to cystic fibrosis, a disease that impairs breathing and digestion. Conversely, hyperactive CFTR proteins can result in excessive fluid transport, causing secretory diarrhea.
Using advanced cryogenic electron microscopy (cryo-EM), Professor Tzyh-Chang Hwang from the Institute of Pharmacology and his team successfully mapped the complete structure of the CFTR protein. They identified how specific inhibitors bind to CFTR, triggering structural changes that reduce activity. This mechanism provides a new explanation for previously unexplained pharmacological effects and offers valuable insights for developing CFTR-targeted therapies.
Interestingly, while pigs also possess CFTR proteins, the same inhibitors that are effective in humans show limited efficacy in pigs. To unravel this mystery, the research team swapped structural segments of the CFTR protein between humans and pigs.
The results showed that pig CFTR proteins began responding to inhibitors similarly to human CFTR proteins, demonstrating how minor structural differences can significantly impact drug responses.
“Observing cellular functions at the molecular and atomic levels has always been my scientific dream,” said Professor Huang. He emphasized that past medical research often focused on organ or cellular scales, limiting understanding of disease mechanisms and drug action principles. Such limitations hindered the development of next-generation therapies.
Professor Huang highlighted that while most drugs target proteins, the lack of precise knowledge about how these drugs interact with their protein targets has been a significant challenge. Cryo-EM technology now enables scientists to decode protein structures with unprecedented accuracy, unlocking new possibilities for structure-based drug design.
The team’s groundbreaking findings, titled “Allosteric Inhibition of CFTR Gating by CFTRinh-172 Binding in the Pore,” were published in Nature Communications, marking a significant advancement in the scientific understanding of CFTR regulation and its role in rare diseases like cystic fibrosis. Leveraging cutting-edge structural biology, this research is poised to accelerate the development of targeted therapies for conditions such as cystic fibrosis, secretory diarrhea, and polycystic kidney disease, offering renewed hope to patients worldwide.
