TY - JOUR
T1 - Cystic fibrosis
T2 - A brief look at some highlights of a decade of research focused on elucidating and correcting the molecular basis of the disease
AU - Ko, Young Hee
AU - Pedersen, Peter L.
N1 - Funding Information:
The authors are most grateful for consistent support from the NIH (Grant DK 43962) to PLP that has supported much of our work and that of previous colleagues. The authors are grateful also for earlier support from the CF foundation (PLP and YHK) and from the American Lung Association, Maryland Division (YHK).
PY - 2001
Y1 - 2001
N2 - The disease Cystic Fibrosis (CF) is caused by mutations in the protein called CFTR, cystic fibrosis transmembrane conductance regulator, an ABC-transporter-like protein found in the plasma membrane of animal cells. CFTR is believed to function primarily as a Cl- channel, but evidence is mounting that this protein has other roles as well. Structurally, CFTR consists of a single polypeptide chain (1480 amino acids) that folds into 5 distinct domains. These include 2 transmembrane domains that are involved in channel formation; 2 nucleotide-binding domains (NBF1 and NBF2), the first of which clearly binds and hydrolyzes ATP; and 1 regulatory domain (R) that is phosphorylated in a cAMP-dependent process. Currently, the 3D structure of neither CFTR nor its domains has been elucidated, although both nucleotide domains have been modeled in 3D, and solution structures in 3D have been obtained for peptide segments of NBF1. The most common mutation causing CF is the deletion (Δ) of a single phenylalanine (F) in position 508 within a putative helix located in NBF1. CF patients bearing this ΔF508 mutation frequently experience chronic lung infections, particularly by Pseudomonas aeruginosa, and have a life span that rarely exceeds the age of 30. Since the CFTR gene was cloned and sequenced in 1989, there has been over a decade of research focused on understanding the molecular basis of CF caused by the ΔF508 mutation, with the ultimate objective of using the knowledge gained to carry out additional research designed to correct the underlying defect. In general, this pioneering or "ground roots" research has succeeded according to plan. This brief review summarizes some of the highlights with a focus on those studies conducted in the authors' laboratory. For us, this research has been both exciting and rewarding mainly because the results obtained, despite very limited funding, have provided considerable insight, not only into the chemical, molecular, and pathogenic basis of CF, but have made it possible for us and others to now develop novel, chemically rational, and "cost effective" strategies to identify agents that correct the structural defect in the ΔF508 CFTR protein causing most cases of CF.
AB - The disease Cystic Fibrosis (CF) is caused by mutations in the protein called CFTR, cystic fibrosis transmembrane conductance regulator, an ABC-transporter-like protein found in the plasma membrane of animal cells. CFTR is believed to function primarily as a Cl- channel, but evidence is mounting that this protein has other roles as well. Structurally, CFTR consists of a single polypeptide chain (1480 amino acids) that folds into 5 distinct domains. These include 2 transmembrane domains that are involved in channel formation; 2 nucleotide-binding domains (NBF1 and NBF2), the first of which clearly binds and hydrolyzes ATP; and 1 regulatory domain (R) that is phosphorylated in a cAMP-dependent process. Currently, the 3D structure of neither CFTR nor its domains has been elucidated, although both nucleotide domains have been modeled in 3D, and solution structures in 3D have been obtained for peptide segments of NBF1. The most common mutation causing CF is the deletion (Δ) of a single phenylalanine (F) in position 508 within a putative helix located in NBF1. CF patients bearing this ΔF508 mutation frequently experience chronic lung infections, particularly by Pseudomonas aeruginosa, and have a life span that rarely exceeds the age of 30. Since the CFTR gene was cloned and sequenced in 1989, there has been over a decade of research focused on understanding the molecular basis of CF caused by the ΔF508 mutation, with the ultimate objective of using the knowledge gained to carry out additional research designed to correct the underlying defect. In general, this pioneering or "ground roots" research has succeeded according to plan. This brief review summarizes some of the highlights with a focus on those studies conducted in the authors' laboratory. For us, this research has been both exciting and rewarding mainly because the results obtained, despite very limited funding, have provided considerable insight, not only into the chemical, molecular, and pathogenic basis of CF, but have made it possible for us and others to now develop novel, chemically rational, and "cost effective" strategies to identify agents that correct the structural defect in the ΔF508 CFTR protein causing most cases of CF.
KW - ABC transporter
KW - CF drug screening
KW - CF drugs
KW - CFTR
KW - Cystic fibrosis
KW - Ion channel
KW - Lung infections
KW - Nucleotide domain
KW - Protein folding
KW - Rational drug design
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U2 - 10.1023/A:1012831322753
DO - 10.1023/A:1012831322753
M3 - Article
C2 - 11804193
AN - SCOPUS:0035689097
SN - 0145-479X
VL - 33
SP - 513
EP - 521
JO - Journal of Bioenergetics and Biomembranes
JF - Journal of Bioenergetics and Biomembranes
IS - 6
ER -