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September 27, 2012
EMBL Chemical Biology: How Receptors Really Work
The latest talk is from Alanna Schepartz of Yale. I had a chance to ride in from the airport with her yesterday, and she gave me a brief preview of her talk, which is on transport of both molecules and information through the plasma membrane of cells. "Some molecules weren't paying attention when Lipinski's rules came down", she says (Lipinski himself was supposed to be here, but had to cancel at the last minute, BTW).
The example here is the EGF receptor. We know a fair amount about the extracellular domain of this protein, and some about the intracellular part. But the "juxtamembrane" portion connecting the two is more of a mystery, although it's clearly crucial for receptor signaling. Her lab has been using a fluorescent marker for particular protein coil structures. What this work seems to show is that different ligands for EGFR (EGF versus TGF-alpha), which are known to produce different downstream signaling, do so through different structures of the protein. Subtle variations of the coiled-coil helical protein on the intracellular face are meaningful and provide yet another way for these receptors to vary their function.
You'd think that there would have to be some such structural difference, since the two "agonists" do act differently. But actually getting a look at it in action is something else again. This is, to me, another example of "treat the protein as a big molecule" thinking. People who do structure-based drug discovery are used to that viewpoint, but not all molecular and cell biologists are. They'll find chemistry infiltrating their worldview, is my prediction. . .
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