Exploring the Mechanism behind G551D and the Effects of Ivacaftor - Abstract
Much research has been done to explain the mechanism behind the third most common cause of Cystic Fibrosis (CF), a missense mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The G551D mutation is caused by a glycine to aspartic acid substitution at the 551st position of the CFTR protein. This causes a malfunctioning in the diffusion of chloride anions across specific cell membranes. A missense mutation involving an amino acid other than Glycine will result a 100x lower probability in the opening of the chloride channel. This is because the mechanism behind G551D-CFTR is multi-faceted and requires that the amino acid filling this position not possess a side chain and/or be negatively charged. The presence of a mutation at Position 511 impairs ATP’s ability to effectively bind at the NBD. Once ATP is able to bind, it is often prohibited from releasing and allowing another ATP molecule to bind in its place. This causes an ineffective conductance of current that prevents the channel from fully opening. Ivacaftor is a drug formulated to increase the potentiation of the CFTR to increase the transference of chloride anions across the cell membrane. It has the ability to provide relief to this subset of CF patients. While we know much about the effects of the drug, research is still being conducted to enhance its efficacy. The use of Ivacaftor has a promising future. However, there are still areas of its use that we still don’t know and, as lung function declines and infections go uncontrolled, its ability to provide relief to patients with the G551D mutation begins to diminish. This paper will elaborate of the mechanism behind the G551D missense mutation and how Ivacaftor can be used to improve the lung function and quality of life of patients with this fatal disease.