CFTR F508del - Interactive 3D Structure Demo

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Highlighted residue (C-alpha) NBD1 ICL4 (cytoplasmic loop 1035-1095) Rest of CFTR

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Residue

Phe 508

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Structure

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What F508del does

CFTR is a chloride and bicarbonate channel at the surface of epithelial cells in the lungs, pancreas, intestine and sweat glands. F508del is a deletion of three DNA bases that removes a single amino acid, phenylalanine 508, from the first nucleotide-binding domain (NBD1). It is the most common variant that causes cystic fibrosis.

Phe508 sits on the NBD1 surface where it packs against the fourth intracellular loop (ICL4) of the second membrane domain. In this model its closest neighbours include Trp496, Arg560, Leu1065, Phe1068, Arg1070 and Phe1074 (see Interface Lock).

Losing Phe508 has two linked effects reported in the literature: NBD1 itself folds less efficiently, and NBD1 docks poorly against ICL4. Most of the mutant protein is recognised as misfolded by cellular quality control in the endoplasmic reticulum and degraded, so much less CFTR reaches the cell surface, and the channel that does arrive is less stable and opens less often.

Small-molecule "correctors" (for example elexacaftor and tezacaftor, combined with the "potentiator" ivacaftor in the approved therapy Trikafta) help more F508del protein fold and reach the cell surface. These medicines treat the underlying protein defect; they are not a cure.

Structures shown are models: the AlphaFold entry is a computational prediction of the normal (wild-type) protein, and 6MSM is an experimental structure of a phosphorylated, ATP-bound CFTR construct carrying the E1371Q mutation. Neither shows the F508del protein itself; the highlight marks where the deleted residue sits. For education and illustration only, not medical advice.