Molecular dynamics and functional characterization of I37R-CFTR lasso mutation provide insights into channel gating activity.
Biochemistry
Pharmacology
Structural biology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
21 Jan 2022
21 Jan 2022
Historique:
received:
26
08
2021
revised:
27
11
2021
accepted:
28
12
2021
entrez:
24
1
2022
pubmed:
25
1
2022
medline:
25
1
2022
Statut:
epublish
Résumé
Characterization of I37R, a mutation located in the lasso motif of the CFTR chloride channel, was conducted by theratyping several CFTR modulators from both potentiator and corrector classes. Intestinal current measurements in rectal biopsies, forskolin-induced swelling (FIS) in intestinal organoids, and short circuit current measurements in organoid-derived monolayers from an individual with I37R/F508del CFTR genotype demonstrated that the I37R-CFTR results in a residual function defect amenable to treatment with potentiators and type III, but not type I, correctors. Molecular dynamics of I37R using an extended model of the phosphorylated, ATP-bound human CFTR identified an altered lasso motif conformation which results in an unfavorable strengthening of the interactions between the lasso motif, the regulatory (R) domain, and the transmembrane domain 2 (TMD2). Structural and functional characterization of the I37R-
Identifiants
pubmed: 35072004
doi: 10.1016/j.isci.2021.103710
pii: S2589-0042(21)01680-1
pmc: PMC8761696
doi:
Types de publication
Journal Article
Langues
eng
Pagination
103710Informations de copyright
© 2021 The Author(s).
Déclaration de conflit d'intérêts
SAW is the recipient of a Vertex Innovation Grant (2018) and a TSANZ/Vertex Research Award (2020). Both are unrelated and outside of the submitted manuscript. AJ has received consulting fees from Vertex on projects unrelated to this study. CYO has acted as consultant and is on advisory boards for Vertex pharmaceuticals. These works are unrelated to this project and manuscript. All other authors declare no conflict of interest.
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