The latest discovery opens up new ways and possibilities in treating CF, which affects approximately 30,000 people in the US in which the median age of survival for is the early 30s.
The findings, published in the November 4 advance online publication of theJournal of Biological Chemistry, investigated the Cystic FibrosisTransmembrane conductance Regulator (CFTR) protein, specifically the nucleotide binding domain 1 (NBD1).
Researchers discovered the most common inherited mutation causing CF creates a small, but critical change in the surface of NBD1 that may alter the way this domain of the CFTR protein interacts with other domains of CFTR. It also could influence the way the CFTR protein interacts with other important regulatory proteins in the cells of people living with CF.
The work done by SGX scientists represents the first time that the NBD1 of humanCFTR has been solved and this new discovery is expected to guide additionalresearch needed to discover an effective treatment for CF.
In the past, developing drugs that addressed a large conformational change to CFTR proved unsuccessful, it may be more feasible to develop drugs that target this small newly discovered change.
The discovery could influence the way the CFTR protein interacts with other important regulatory proteins in the cells of people living with CF. Ninety percent of people with CF carry this common type of disease-causing mutation, identified as Delta F508, in the NBD1 region of the CFTR protein.
Robert Beall, chief executive officer of the CF Foundation said: "SGX's first-ever determination of the crystal structure of the disease-causing mutant form of NBD1 is an important finding and a strong foundation for our future drug discovery and development initiatives."
"While many of our drug development initiatives still are viable potential therapies, this discovery will help us narrow our search for drug candidates that address this specific change."
Cystic fibrosis, also known as mucoviscidosis, is one of the most common genetic diseases with a fatal outcome in western Europe. A defective gene that affects the salt and fluid composition of respiratory tract secretions causes the disease. As a result, they become highly viscous. The viscous mucous then clumps in the smaller lung passages.
Stephen Burley, chief scientific officer of SGX said: "With drug targets as challenging as the CFTR protein, experimentally determined structures will be invaluable as they allow researchers to see in three-dimensions precisely how small molecules bind to the target protein and help correct functional defects arising from disease-causing mutations."