| Structural highlights
Disease
[CFTR_HUMAN] Defects in CFTR are the cause of cystic fibrosis (CF) [MIM:219700]; also known as mucoviscidosis. CF is the most common genetic disease in the Caucasian population, with a prevalence of about 1 in 2'000 live births. Inheritance is autosomal recessive. CF is a common generalized disorder of exocrine gland function which impairs clearance of secretions in a variety of organs. It is characterized by the triad of chronic bronchopulmonary disease (with recurrent respiratory infections), pancreatic insufficiency (which leads to malabsorption and growth retardation) and elevated sweat electrolytes.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] Defects in CFTR are the cause of congenital bilateral absence of the vas deferens (CBAVD) [MIM:277180]. CBAVD is an important cause of sterility in men and could represent an incomplete form of cystic fibrosis, as the majority of men suffering from cystic fibrosis lack the vas deferens.[47] [48] [49] [50] [:]
Function
[CFTR_HUMAN] Involved in the transport of chloride ions. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the SLC4A7 transporter. Can inhibit the chloride channel activity of ANO1.[51]
Publication Abstract from PubMed
Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve folding of CFTR and potentiators that recover the function of CFTR. Here, we report two cryo-electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)-approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds.
Structural identification of a hotspot on CFTR for potentiation.,Liu F, Zhang Z, Levit A, Levring J, Touhara KK, Shoichet BK, Chen J Science. 2019 Jun 21;364(6446):1184-1188. doi: 10.1126/science.aaw7611. PMID:31221859[52]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Jones CT, McIntosh I, Keston M, Ferguson A, Brock DJ. Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation. Hum Mol Genet. 1992 Apr;1(1):11-7. PMID:1284466
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- ↑ Greil I, Wagner K, Rosenkranz W. A new missense mutation G1249E in exon 20 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Hered. 1994 Jul-Aug;44(4):238-40. PMID:7520022
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- ↑ Schaedel C, Kristoffersson AC, Kornfalt R, Holmberg L. A novel cystic fibrosis mutation, Y109C, in the first transmembrane domain of CFTR. Hum Mol Genet. 1994 Jun;3(6):1001-2. PMID:7524909
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- ↑ Leoni GB, Pitzalis S, Podda R, Zanda M, Silvetti M, Caocci L, Cao A, Rosatelli MC. A specific cystic fibrosis mutation (T3381) associated with the phenotype of isolated hypotonic dehydration. J Pediatr. 1995 Aug;127(2):281-3. PMID:7543567
- ↑ Ferec C, Novelli G, Verlingue C, Quere I, Dallapiccola B, Audrezet MP, Mercier B. Identification of six novel CFTR mutations in a sample of Italian cystic fibrosis patients. Mol Cell Probes. 1995 Apr;9(2):135-7. PMID:7541510
- ↑ Messaoud T, Verlingue C, Denamur E, Pascaud O, Quere I, Fattoum S, Elion J, Ferec C. Distribution of CFTR mutations in cystic fibrosis patients of Tunisian origin: identification of two novel mutations. Eur J Hum Genet. 1996;4(1):20-4. PMID:8800923
- ↑ Nasr SZ, Strong TV, Mansoura MK, Dawson DC, Collins FS. Novel missense mutation (G314R) in a cystic fibrosis patient with hepatic failure. Hum Mutat. 1996;7(2):151-4. PMID:8829633 doi:<151::AID-HUMU10>3.0.CO;2-1 10.1002/(SICI)1098-1004(1996)7:2<151::AID-HUMU10>3.0.CO;2-1
- ↑ Petreska L, Plaseska D, Koceva S, Stavljenic-Rukavina A, Efremov GD. A novel mutation in exon 12 (Y569C) of the CFTR gene identified in a patient of Croatian origin. Hum Mutat. 1996;7(4):374-5. PMID:8723693 doi:10.1002/humu.1380070402
- ↑ Bienvenu T, Chertkoff L, Beldjord C, Segal E, Carniglia L, Barreiro C, Kaplan JC. Identification of three novel mutations in the cystic fibrosis transmembrane conductance regulator gene in Argentinian CF patients. Hum Mutat. 1996;7(4):376-7. PMID:8723695 doi:<376::AID-HUMU18>3.0.CO;2-# 10.1002/(SICI)1098-1004(1996)7:4<376::AID-HUMU18>3.0.CO;2-#
- ↑ Hughes DJ, Hill AJ, Macek M Jr, Redmond AO, Nevin NC, Graham CA. Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes. Hum Mutat. 1996;8(4):340-7. PMID:8956039 doi:<340::AID-HUMU7>3.0.CO;2-B 10.1002/(SICI)1098-1004(1996)8:4<340::AID-HUMU7>3.0.CO;2-B
- ↑ Clavel C, Pennaforte F, Pigeon F, Verlingue C, Birembaut P, Ferec C. Identification of four novel mutations in the cystic fibrosis transmembrane conductance regulator gene: E664X, 2113delA, 306delTAGA, and delta M1140. Hum Mutat. 1997;9(4):368-9. PMID:9101301 doi:<368::AID-HUMU13>3.0.CO;2-0 10.1002/(SICI)1098-1004(1997)9:4<368::AID-HUMU13>3.0.CO;2-0
- ↑ Gouya L, Pascaud O, Munck A, Elion J, Denamur E. Novel mutation (A141D) in exon 4 of the CFTR gene identified in an Algerian patient. Hum Mutat. 1997;10(1):86-7. PMID:9222768 doi:<86::AID-HUMU15>3.0.CO;2-W 10.1002/(SICI)1098-1004(1997)10:1<86::AID-HUMU15>3.0.CO;2-W
- ↑ Casals T, Pacheco P, Barreto C, Gimenez J, Ramos MD, Pereira S, Pinheiro JA, Cobos N, Curvelo A, Vazquez C, Rocha H, Seculi JL, Perez E, Dapena J, Carrilho E, Duarte A, Palacio AM, Nunes V, Lavinha J, Estivill X. Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients. Hum Mutat. 1997;10(5):387-92. PMID:9375855 doi:<387::AID-HUMU9>3.0.CO;2-C 10.1002/(SICI)1098-1004(1997)10:5<387::AID-HUMU9>3.0.CO;2-C
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- ↑ Onay T, Topaloglu O, Zielenski J, Gokgoz N, Kayserili H, Camcioglu Y, Cokugras H, Akcakaya N, Apak M, Tsui LC, Kirdar B. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998 Feb;102(2):224-30. PMID:9521595
- ↑ Bombieri C, Benetazzo M, Saccomani A, Belpinati F, Gile LS, Luisetti M, Pignatti PF. Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease. Hum Genet. 1998 Dec;103(6):718-22. PMID:9921909
- ↑ Vankeerberghen A, Wei L, Jaspers M, Cassiman JJ, Nilius B, Cuppens H. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 Oct;7(11):1761-9. PMID:9736778
- ↑ Malone G, Haworth A, Schwarz MJ, Cuppens H, Super M. Detection of five novel mutations of the cystic fibrosis transmembrane regulator (CFTR) gene in Pakistani patients with cystic fibrosis: Y569D, Q98X, 296+12(T>C), 1161delC and 621+2(T>C). Hum Mutat. 1998;11(2):152-7. PMID:9482579 doi:<152::AID-HUMU8>3.0.CO;2-L 10.1002/(SICI)1098-1004(1998)11:2<152::AID-HUMU8>3.0.CO;2-L
- ↑ Leoni GB, Pitzalis S, Tonelli R, Cao A. Identification of a novel mutation (S13F) in the CFTR gene in a CF patient of Sardinian origin. Hum Mutat. 1998;11(4):337. PMID:9554753
- ↑ Feldmann D, Sardet A, Cougoureux E, Plouvier E, Fontaine JL, Tournier G, Aymard P. Identification of three novel mutations in the CFTR gene, R117P, deltaD192, and 3121-1G-->A in four French patients. Hum Mutat. 1998;Suppl 1:S78-80. PMID:9452048
- ↑ Casals T, Ramos MD, Gimenez J, Nadal M, Nunes V, Estivill X. Paternal origin of a de novo novel CFTR mutation (L1065R) causing cystic fibrosis. Hum Mutat. 1998;Suppl 1:S99-102. PMID:9452054
- ↑ Shackleton S, Harris A. A 2-amino acid insertion mutation (1243insACAAAA) in exon 7 of the CFTR gene. Hum Mutat. 1998;Suppl 1:S156-7. PMID:9452073
- ↑ Picci L, Cameran M, Olante P, Zacchello F, Scarpa M. Identification of a D579G homozygote cystic fibrosis patient with pancreatic sufficiency and minor lung involvement. Mutations in brief no. 221. Online. Hum Mutat. 1999;13(2):173. PMID:10094564 doi:<173::AID-HUMU19>3.0.CO;2-E 10.1002/(SICI)1098-1004(1999)13:2<173::AID-HUMU19>3.0.CO;2-E
- ↑ Mercier B, Verlingue C, Lissens W, Silber SJ, Novelli G, Bonduelle M, Audrezet MP, Ferec C. Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients. Am J Hum Genet. 1995 Jan;56(1):272-7. PMID:7529962
- ↑ Jezequel P, Dorval I, Fergelot P, Chauvel B, Le Treut A, Le Gall JY, Le Lannou D, Blayau M. Structural analysis of CFTR gene in congenital bilateral absence of vas deferens. Clin Chem. 1995 Jun;41(6 Pt 1):833-5. PMID:7539342
- ↑ Zielenski J, Patrizio P, Markiewicz D, Asch RH, Tsui LC. Identification of two mutations (S50Y and 4173delC) in the CFTR gene from patients with congenital bilateral absence of vas deferens (CBAVD). Hum Mutat. 1997;9(2):183-4. PMID:9067761 doi:<183::AID-HUMU13>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1997)9:2<183::AID-HUMU13>3.0.CO;2-Z
- ↑ Bienvenu T, Bousquet S, Vidaud D, Hubert D, Francoual C, Beldjord C, Kaplan JC. A novel missense mutation D513G in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified in a French CBAVD patient. Mutations in brief no. 175. Online. Hum Mutat. 1998;12(3):213-4. PMID:10651488
- ↑ Ousingsawat J, Kongsuphol P, Schreiber R, Kunzelmann K. CFTR and TMEM16A are separate but functionally related Cl- channels. Cell Physiol Biochem. 2011;28(4):715-24. doi: 10.1159/000335765. Epub 2011 Dec, 14. PMID:22178883 doi:10.1159/000335765
- ↑ Liu F, Zhang Z, Levit A, Levring J, Touhara KK, Shoichet BK, Chen J. Structural identification of a hotspot on CFTR for potentiation. Science. 2019 Jun 21;364(6446):1184-1188. doi: 10.1126/science.aaw7611. PMID:31221859 doi:http://dx.doi.org/10.1126/science.aaw7611
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