Can two wrongs make a right? F508del-CFTR ion channel rescue by second-site mutations in its transmembrane domains

Abstract

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Virtual Drug Repositioning as a Tool to Identify Natural Small Molecules That Synergize with Lumacaftor in F508del-CFTR Binding and Rescuing

“…In wild-type CFTR, W496 forms a hydrophobic cluster with F508 itself, F1068, and, partially, with F1074 [ 51 ]. Moreover, in full agreement with the recently published paper by Prins et al [ 54 ], NAM also interacts with L1065, a revertant residue able to partially rescue F508 deletion. Furthermore, the binding of NAM to R1070 could have biological importance.…”

“…The hydrophobic interactions between the NAM’s pyridine moiety and residues W496 and L1065, both located in the ICL4 loop, might help in restoring this compromised interaction between ICL4 and NBD1. According to our calculations, NAM is able to restate that interaction between W496 and F508, which is lost after mutation, and in addition is able to interact with L1065, a residue recently defined as able to revert F508del mutation effects on CFTR [ 54 ].…”

“…Here, by a dedicated pipeline, a drug repositioning study supported by molecular docking and dynamics predicted NAM to bind to F508del-CFTR into the lumacaftor binding pocked DP1 located in the NBD1 domain and partially interfaced with the ICL4 domain, a dynamic interface crucial for CFTR gating [ 54 ]. Interestingly, NAM created a hydrophobic interaction with W496 and L1065.…”

Mutation accumulation in H. sapiens F508del CFTR countermands dN/dS type genomic analysis

“…Another potential confounder involves the possibility of second site suppressors that partially rescue F508del CFTR. Known suppressors have been studied by our laboratory and others to characterize CFTR molecular abnormalities [ 21 , 22 , 50 – 54 ], and if present in cis with F508del could restore CFTR activity. Suppressors of F508del include R1070W, F1068M, F1074M, V510D/E/A, I539T, G550E, R553M/Q, and R555K [ 21 , 22 , 50 – 55 ].…”

“…(The protein is inactive; an argument that new SNPs on an F508del allele might elicit additional fitness effects would contradict much of what has been learned regarding CFTR during the past 30 years.) Moreover, the F508del protein has been extensively evaluated for partial suppressor mutations, and although a few such SNPs are known, none are germane to analysis presented here [ 21 , 22 ] (see also below).…”