Cel
The CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) is a unique ABC protein functioning as a chloride channel. It consists of two transmembrane and two nucleotide binding domains, and a regulatory region. The cftr gene is mutated in cystic fibrosis, an inherited disease of high morbidity and mortality mostly affecting people with European ancestors. So far more than 1,500 mutations are known affecting the stability or the function of the protein that results in the lack of functional channels in the cell membrane. This leads to imbalanced water and salt homeostasis affecting the function of all organs with secretory epithelia. Therefore it is important to develop therapeutic agents to stabilize CFTR and restore its function. This is being done by blind screening resulting in compounds that are hydrophobic and act on either the transmembrane or intracellular parts of the protein. In this study we aim to modulate the stability and function of CFTR from the extracellular side. The advantage of this approach is the targeting of the hydrophilic extracellular loops that enable structural studies and design of water soluble drugs with advantageous toxological properties. We will employ cutting-edge computational approaches combined with solid experimental methods to gain insights in the structure and dynamics of the larger extracellular loops in CFTR. The effects of the extracellular loops on the conformation of the transmembrane region and the protein function will be studied that will establish a basis for rational drug design. Our preliminary results indicate that the extracellular loops possess stable secondary structural elements and changes in their conformation can either stimulate or inhibit the protein function. Together, the extracellular loops will provide a focused target to restore CFTR stability and function. Moreover, this approach can be also applied to rationally modulate the function of other ABC proteins involved in human diseases.
Dziedzina nauki
Słowa kluczowe
Zaproszenie do składania wniosków
FP7-PEOPLE-IRG-2008
Zobacz inne projekty w ramach tego zaproszenia
System finansowania
MC-IRG - International Re-integration Grants (IRG)Koordynator
1052 BUDAPEST
Węgry