8EIO

The complex of phosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) with elexacaftor (VX-445), lumacaftor (VX-809) and ATP/Mg

Summary for 8EIO

• Entry DOI: 10.2210/pdb8eio/pdb
• EMDB information: 28160
• Descriptor: Cystic fibrosis transmembrane conductance regulator, MAGNESIUM ION, ADENOSINE-5'-TRIPHOSPHATE, ... (8 entities in total)
• Functional Keywords: abc transporter, ion channel, folding correction, membrane protein, atp-binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 172322.11

Authors

Fiedorczuk, K.,Chen, J. (deposition date: 2022-09-15, release date: 2022-10-19, Last modification date: 2025-05-21)

Primary citation

Fiedorczuk, K.,Chen, J.
Molecular structures reveal synergistic rescue of Delta 508 CFTR by Trikafta modulators.
Science, 378:284-290, 2022

PubMed Abstract: The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis and function. The advanced therapy Trikafta combines the folding corrector tezacaftor (VX-661), the channel potentiator ivacaftor (VX-770), and the dual-function modulator elexacaftor (VX-445). However, it is unclear how elexacaftor exerts its effects, in part because the structure of Δ508 CFTR is unknown. Here, we present cryo-electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators. When used alone, elexacaftor partially rectified interdomain assembly defects in Δ508 CFTR, but when combined with a type I corrector, did so fully. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function.

PubMed: 36264792
DOI: 10.1126/science.ade2216

Experimental method

ELECTRON MICROSCOPY (2.8 Å)