摘要：SummaryCharacterization 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-CFTRmutation increases understanding of CFTR channel regulation and provides a potential pathway to expand drug access to CF patients with ultra-rare genotypes.Graphical abstractDisplay OmittedHighlights•I37R-CFTR localizes to the cell surface and results in a residual function defect•I37R-CFTR breaks a conserved salt bridge perturbing the lasso motif•I37R-CFTR strengthens lasso interaction with the R domain, impacting channel gating•I37R-CFTR is responsive to potentiators (GLPG1837) and class III correctors (VX-445)Pharmacology; Biochemistry; Structural biology
