Cystic fibrosis (CF) is a rare genetic disease caused by mutations in the cystic fibrosis
transmembrane conductance regulator (CFTR), an epithelial anion channel expressed in several vital
organs. Absence of functional CFTR results in imbalanced osmotic equilibrium and subsequent
mucus build up in the lungs-which increases the risk of infection and eventually causes death. CFTR is
an ATP-binding cassette (ABC) transporter family protein composed of two transmembrane domains
(TMDs), two nucleotide binding domains (NBDs), and an unstructured regulatory domain. The most
prevalent patient mutation is the deletion of F508 (F508del), making F508del CFTR the primary target
for current FDA approved CF therapies. However, no experimental multi-domain F508del CFTR
structure has been determined and few studies have modeled F508del using multi-domain WT CFTR
structures. Here, we used cryo-EM density data and Rosetta comparative modeling (RosettaCM) to
compare a F508del model with published experimental data on CFTR NBD1 thermodynamics. We
then apply this modeling method to generate multi-domain WT and F508del CFTR structural models.
These models demonstrate the destabilizing effects of F508del on NBD1 and the NBD1/TMD interface
in both the inactive and active conformation of CFTR. Furthermore, we modeled F508del/R1070W
and F508del bound to the CFTR corrector VX-809. Our models reveal the stabilizing effects of VX-809
on multi-domain models of F508del CFTR and pave the way for rational design of additional drugs
that target F508del CFTR for treatment of CF.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:85994 |
| Date | 13 June 2023 |
| Creators | McDonald, Eli Fritz, Woods, Hope, Smith, Shannon T., Kim, Minsoo, Schröder, Clara T., Plate, Lars, Meiler, Jens |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 471 |
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