CFTR Potentiators & Correctors
04/09/10 11:35
Let’s talk about VX809 and VX770--
First of all, one (VX-809) is a “corrector” molecule for the F508 variant. That particular mutant protein, as you might recall, has a problem with trafficking to the membrane of the cell. That’s it MAIN problem: it’s “misfolded” and the quality control members of the endoplasmic reticulum don’t let it out of that protein making organelle, and it’s cut up into it’s amino acid pieces. VX-809 “corrects” the protein enough so that some of it gets to the membrane, to do it’s job.
But, F508 has another problem—even after it gets to the membrane of the cell, it can’t transport anions very well. Something is wrong with it’s ability to be activated. (It’s got a major problem with it’s nucleotide binding domains, but that’s the topic for another discussion). This is where VX-770 comes into play.
VX-770 is a “potentiator” molecule. Simply put, the problem with G551D’s activation, and it’s ability to move anions out, is corrected by this small molecule. This variant of the CFTR protein has a mutation in one of it’s ATP binding sites (the CFTR requires ATP to open, and to transport anions).
So? What does all of this mean to you? Well, let me tell you:
They have tested G551D patients with VX-770, and it improves lung function. They have tested VX-809 in F508 patients and it doesn’t improve lung function, but it increases chloride conductance. That means that, although they can use VX-809 to get the misfolded CFTR F508 protein to the membrane, once there, it isn’t activated like it should be.
So, they are going to try using both of them at the same time. They think that the VX-809 will get the mutant F508 to the membrane, where it belongs, and once it’s there, they’ll use VX-770 to activate it.
What is the assumption here, then? The assumption is that the gating defects of both proteins are caused by the same thing.
That brings us to our next subject: nucleotide binding domains. The CFTR has two of them: NBD1 and NBD2. Hydrolysis (water splits it and it turns into another molecule; in this case ADP) of ATP at NBD1 opens the channel. NBD2 is responsible for the regulating the closing of the channel. BUT, these binding domains “talk” to each other. There may be some kind of feedback loop here (probably has to do with the fact that this protein moves out negatively charged ions, but I won’t get into that here). It might also be that NBD1 is responsible for opening and closing the channel (think of it like a person whose only job is to hold on to the doorknob) and NBD2 regulates how long the channel stays open (think of it like a person whose only job is to tell the guy who is holding the door knob to push or pull on it).
Where is the mutation affecting gating in the F508 variant? Where is the mutation affecting gating in the G551D variant? If they are both in NBD1, then what are they? How do they affect how NBD1 works?
First of all, one (VX-809) is a “corrector” molecule for the F508 variant. That particular mutant protein, as you might recall, has a problem with trafficking to the membrane of the cell. That’s it MAIN problem: it’s “misfolded” and the quality control members of the endoplasmic reticulum don’t let it out of that protein making organelle, and it’s cut up into it’s amino acid pieces. VX-809 “corrects” the protein enough so that some of it gets to the membrane, to do it’s job.
But, F508 has another problem—even after it gets to the membrane of the cell, it can’t transport anions very well. Something is wrong with it’s ability to be activated. (It’s got a major problem with it’s nucleotide binding domains, but that’s the topic for another discussion). This is where VX-770 comes into play.
VX-770 is a “potentiator” molecule. Simply put, the problem with G551D’s activation, and it’s ability to move anions out, is corrected by this small molecule. This variant of the CFTR protein has a mutation in one of it’s ATP binding sites (the CFTR requires ATP to open, and to transport anions).
So? What does all of this mean to you? Well, let me tell you:
They have tested G551D patients with VX-770, and it improves lung function. They have tested VX-809 in F508 patients and it doesn’t improve lung function, but it increases chloride conductance. That means that, although they can use VX-809 to get the misfolded CFTR F508 protein to the membrane, once there, it isn’t activated like it should be.
So, they are going to try using both of them at the same time. They think that the VX-809 will get the mutant F508 to the membrane, where it belongs, and once it’s there, they’ll use VX-770 to activate it.
What is the assumption here, then? The assumption is that the gating defects of both proteins are caused by the same thing.
That brings us to our next subject: nucleotide binding domains. The CFTR has two of them: NBD1 and NBD2. Hydrolysis (water splits it and it turns into another molecule; in this case ADP) of ATP at NBD1 opens the channel. NBD2 is responsible for the regulating the closing of the channel. BUT, these binding domains “talk” to each other. There may be some kind of feedback loop here (probably has to do with the fact that this protein moves out negatively charged ions, but I won’t get into that here). It might also be that NBD1 is responsible for opening and closing the channel (think of it like a person whose only job is to hold on to the doorknob) and NBD2 regulates how long the channel stays open (think of it like a person whose only job is to tell the guy who is holding the door knob to push or pull on it).
Where is the mutation affecting gating in the F508 variant? Where is the mutation affecting gating in the G551D variant? If they are both in NBD1, then what are they? How do they affect how NBD1 works?