M2 quiz: select the correct adamantane binding model.
Adamantane drugs inhibit the M2 proton channel from influenza A, a tiny tetrameric protein that equalizes pH between the virus and the endosome of the cell that has swallowed it. Over the past few years a great deal of structural evidence has accumulated showing how adamantane drugs work. Problem is that the evidence supports two different models of M2 inhibition. “Discount Thoughts” provides a great review on a mechanism that is truly a tough nut to crack.
To the left: a crystal structure supporting a pore blocking model in which adamantane binds in the middle of the four TM helices. To the right: an NMR structure supporting an alternative “dynamic quenching model” in which rimantadine blocks the channel by stabilizing the helices.
Figures adapted from Discount Thoughts
What do you think is the correct model? Tell us in the comments.
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Just as a reminder that in the crystal structure paper is also included a very high resolution crystal structure (2.00 A) of the unliganded M2TM form.
Focus is being wrongly placed on choosing which structure is right and which structure is wrong. There are 25 years of literature that identify the position of the drug binding site. Less time should be spent debating and more time doing science.