This post follows my previous post about VX809 and F508del
How does VX809 help F508del?
A recent study by Ren et al. (2013) suggests that VX809 acts on membrane spanding domain one (MSD1), and that the action on MSD1 partially suppressors folding defects in F508del by enhancing the interactions between MSD1 with NBD1, MSD2 and NBD2 (see images of the protein below).
How can the level of folding be increased further?
In order to achieve a higher level of F508del correction beyond the level seen with VX809, further stabilization of NBD1 and/or an improvement in the interaction between NBD1 and MSD2 is needed. 50-100% of normal CFTR function can be seen when VX809 is used in combination with approaches that increase the stability of NBD1 or stabilise the interaction between NBD1 and MSD2 (NBD1:ICL4 interface). Interestingly, VX809 is needed in order for these two approaches to have a significant impact on F508del folding (Ren et al. 2013).
VX809 improved the folding of many missense mutations in MSD1
VX809 improved the function of the class 2 mutations E56K, P67L, E92K, L206W, and V232D in this study by Ren et al. (2013). The level of function seen was higher than the level seen with F508del and VX809 (15%). E56K, P67L and L206W were completely corrected, reaching over 100% of normal levels. E92K was completely corrected at a much higher dose. V232D reached a level below 25%, however a previous study found that another corrector, Corr4a, restored V232D to normal levels (Caldwell et al. 2011). VX809 did not help all of the missense mutations in MSD1 that were tested (not listed in the study).
A previous study (He et al. 2012) found that VX809 could also help several mutations in the ICL4 area of MSD2 (H1054D, G1061R, L1065P, Q1071P, L1077P) and also H139R, R258G, and S945L.
Background info about the CFTR channel:
Consists of 1480 sequential amino acids.
Consists of five domains that interact with each other.
1. Membrane spanning domain 1: Hover over the 6 yellow bars here to see the details
2. Nucleotide binding domain 1: Amino acids 433-584 (includes F508del and G551D)
3. Regulatory domain: Amino acids 590-831
4. Membrane spanning domain 2: Hover over the 6 yellow bars here to see the details
5. Nucleotide binding domain 2: Amino acids 1219-1382
There are connecting amino acids in between these domains
A ‘flat’ image of the CFTR channel, showing the domains.
The 3D structure of the channel. The phenylalanine deletion is F508del.