8FZQ
Dehosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
Summary for 8FZQ
| Entry DOI | 10.2210/pdb8fzq/pdb |
| EMDB information | 29637 |
| Descriptor | Cystic fibrosis transmembrane conductance regulator, MAGNESIUM ION, ADENOSINE-5'-TRIPHOSPHATE (3 entities in total) |
| Functional Keywords | ion channel, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 169922.03 |
| Authors | Levring, J.,Terry, D.S.,Kilic, Z.,Fitzgerald, G.A.,Blanchard, S.C.,Chen, J. (deposition date: 2023-01-29, release date: 2023-03-29, Last modification date: 2024-06-19) |
| Primary citation | Levring, J.,Terry, D.S.,Kilic, Z.,Fitzgerald, G.,Blanchard, S.,Chen, J. CFTR function, pathology and pharmacology at single-molecule resolution. Nature, 616:606-614, 2023 Cited by PubMed Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes. Alterations in CFTR cause cystic fibrosis, a fatal disease without a cure. Electrophysiological properties of CFTR have been analysed for decades. The structure of CFTR, determined in two globally distinct conformations, underscores its evolutionary relationship with other ATP-binding cassette transporters. However, direct correlations between the essential functions of CFTR and extant structures are lacking at present. Here we combine ensemble functional measurements, single-molecule fluorescence resonance energy transfer, electrophysiology and kinetic simulations to show that the two nucleotide-binding domains (NBDs) of human CFTR dimerize before channel opening. CFTR exhibits an allosteric gating mechanism in which conformational changes within the NBD-dimerized channel, governed by ATP hydrolysis, regulate chloride conductance. The potentiators ivacaftor and GLPG1837 enhance channel activity by increasing pore opening while NBDs are dimerized. Disease-causing substitutions proximal (G551D) or distal (L927P) to the ATPase site both reduce the efficiency of NBD dimerization. These findings collectively enable the framing of a gating mechanism that informs on the search for more efficacious clinical therapies. PubMed: 36949202DOI: 10.1038/s41586-023-05854-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (4.3 Å) |
Structure validation
Download full validation report
