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The latest addition to the story of the insulin-like growth factors and their receptors is out today in Structure! My contribution was (as usual) in helping with the model building - this was driven by Mike Lawrence& #39;s team at @WEHI_research
https://www.cell.com/structure/fulltext/S0969-2126(20)30171-4">https://www.cell.com/structure... (1/9)
https://www.cell.com/structure/fulltext/S0969-2126(20)30171-4">https://www.cell.com/structure... (1/9)
This family is both the holder of a special place in my heart as my entry-point into the world of structural biology, and the source of a certain level of angst in being the trigger for my largely giving up on attempting to *predict* receptor-ligand interactions... (2/9)
Let me try to give you some idea of why. IGF-II looks like this. The residues highlighted in green (particularly the Phe-Tyr-Phe on the left) are critical for receptor binding but appear stable here, in insulin, in IGF-I, free or in complex with carrier proteins. (3/9)
So naturally you& #39;d expect it to just "dock" onto the receptor fairly rigidly, right? Wrong. Here& #39;s what actually happens. These residues pull away, opening up the "C loop" (pointing up), and then the tail end of the receptor *threads itself through it*. I mean, what?? (4/9)
This isn& #39;t just a fluke - the same essential behaviour has now been shown for IGF-I and -II in complex with the IGF-I receptor, and for IGF-I in complex with the insulin receptor, in cryo-EM and crystallographic experiments. (5/9)
Incidentally, it neatly explains (in the weirdest possible way) why one splice variant of the insulin receptor binds IGF-I well while the other doesn& #39;t: the poorly-binding variant has an extension on this "tail", making it simply too long to thread itself through the loop. (6/9)
And then we come to the overall conformational change of the receptor itself. The obvious point of flexibility is the "hinge" connecting the cysteine-rich region to the L2 domain (red)... my prediction was that L1 (bottom) would swing across to engage the opposite leg. (7/9)
Instead, this is what happens. The receptor undergoes a truly *massive* rearrangement to effectively touch its own head, to the point where you have to spend a while looking at it just to convince yourself you& #39;re looking at the same protein. Start: 5u8r; final: 6vwi/j. (8/9)
