Cystic Fibrosis Drugs Can Be ‘Life-Changing’ For Patients. New Images Reveal How These Molecules Work

Good news! Sometimes it takes a decade more more to figure out exactly how a new medication works.

"Just over a decade ago, in one of the great advances in modern medicine, researchers at Aurora Biosciences and then Vertex Pharmaceuticals found what they described at the time as needles in a haystack – small molecule drugs that can treat cystic fibrosis, the lung-damaging genetic disease. ...

a technical breakthrough in 2014, cryogenic electron microscopy. By freezing samples of proteins under study, cryo-EM allowed detailed electron microscope pictures of protein structure and started what has been dubbed the “resolution revolution.” ...
By taking thousands of electron microscope pictures, the scientists showed that CFTR has an unexpected cavity in its 3D structure. These corrector drugs nestle precisely in that hole, stabilizing the protein and ensuring that it folds into the right shape. “It is surprising until you actually see it, because there are no other examples in the literature of how small molecules can help protein folding,”"

Cystic Fibrosis Drugs Can Be ‘Life-Changing’ For Patients. New Images Reveal How These Molecules Work. | HHMI A mutated protein causes the genetic disease cystic fibrosis. Now, researchers have solved the structure of the protein and how certain drugs bind to it, unveiling their mode of action.

Mechanism of CFTR correction by type I folding correctors (open access)

New cryo-electron microscopy images reveal the cystic fibrosis drug Tezacaftor binding to the CFTR protein (left) in a small cavity (right).