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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« EMBL Chemical Biology: Unnatural Amino Acid Labels | Main | EMBL Chemical Biology: Greasy Labels »

September 27, 2012

EMBL Chemical Biology: How Receptors Really Work

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Posted by Derek

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. . .

Comments (5) + TrackBacks (0) | Category: Chemical Biology


COMMENTS

1. biologist on September 27, 2012 7:47 AM writes...

The mouse zenograft model exonerated?

http://clincancerres.aacrjournals.org/content/early/2012/06/28/1078-0432.CCR-12-0738

Antitumor Activity of Targeted and Cytotoxic Agents in Murine Subcutaneous Tumor Models Correlates with Clinical Response

Comments? Derek?

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2. lazybratsche on September 27, 2012 9:14 AM writes...

Cool. Count me as one more molecular biologists who is trying to think more structurally... I'm just diving into study of TGFβ signalling, and there too similar ligands can have dramatically different signalling activity through the same receptor, possibly through subtle allosteric effects.

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3. barry on September 27, 2012 2:36 PM writes...

Nanotechnology is chemistry. And Material Science is chemistry. And Molecular Biology is chemistry. Sure, making up new names for it sometimes shakes loose some grant money. Maybe you can even get a new lab building donated. But don't ever abandon the intellectual tools we've built over the last 200yrs just because you've shed the name of "chemist"

Permalink to Comment

4. Anonymous on September 27, 2012 7:18 PM writes...

And all chemistry is physics....

Permalink to Comment

5. The Powers That Be on September 30, 2012 3:13 PM writes...

And all physics is math...

QED

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