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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: Twitter: Dereklowe

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January 22, 2010

Receptors, Moving and Shaking

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Posted by Derek

I've written here before about how I used to think that I understood G-protein coupled receptors (GPCRs), but that time and experience have proven to me that I didn't know much of anything. One of the factors that's complicated that field is the realization that these receptors can interact with each other, forming dimers (or perhaps even larger assemblies) which presumably are there for some good reason, and can act differently from the classic monomeric form.
A neat paper has appeared in PNAS that gives us some quantitative numbers on this phenomenon, and some great pictures as well. What you're looking at is a good ol' CHO cell, transfected with muscarinic M1 receptors. Twenty years ago (gulp) I was cranking out compounds to tickle cell membranes of this exact type, among others. The receptors are visualized by a fluorescent ligand (telenzepine), and the existence of dimers can be inferred by the "double-intensity" spots shown in the inset.

With this kind of resolution and time scale, the UK team that did this work could watch the receptors wandering over the cell surface in real time. It's a classic random walk, as far as they can tell. Watching the cohort of high-intensity spots, they can see changes as they switch to lower-intensity monomers and back again. Over a two-second period, it appeared that about 81% of the tracks were monomers, 9% were dimers, and 3% changed over during the tracking. (The remaining 7% were impossible to assign with confidence, which makes me wonder what's lurking down there).

They refined the technique by using two differently-fluorescent forms of labeled telenzepine, labeling the cells in a 50/50 ratio, and watching what happens to the red, green, (and combined yellow) spots over time. It looks as if the receptor population is a steady-state mix of monomers and dimers, exchanging on a time scale of seconds. Of course, the question comes up of how different ligands might affect this process, and you could begin to answer that with different fluorescent species. But since the technique depends on having a low-off-rate species bound to the receptor in order to see it, some of the most interesting dynamic questions will have to wait. It's still very nice to actually see these things, though; it gives a medicinal chemist something to picture. . .

Comments (7) + TrackBacks (0) | Category: Biological News


1. trisynthon on January 22, 2010 5:33 PM writes...

Anyone who is as intrigued as I am by this real-time single molecule imaging stuff should check out the review by Sunny Xie: Annu. Rev. Biophys. 2008. 37:417–44. It's an absolute tour de force. This work ain't bad either.

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2. leftscienceawhileago on January 22, 2010 11:08 PM writes...

Derek doesn't mention that they have free movies in the supporting info! Nothing like a movie to give you a real feel for what you are looking at.

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3. Sili on January 23, 2010 10:09 AM writes...

It's probably not a good sign that I have never heard of Chinese Hamster Ovaries ...

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4. Yggdrasil on January 23, 2010 8:17 PM writes...

Perhaps some of the interesting dynamics studies won't have to wait so long. Chemists have developed some methods to covalently label tagged proteins in living cells with "handles" (e.g. biotin, azide groups) to which organic dyes can be attached (for example, see Alice Ting's work on her biotin ligase and lipoic acid ligase systems).

Assuming that these methods can achieve high enough labeling densities and there aren't significant problems with receptor turnover, these technologies could enable these same types of experiments on receptors in their apo or agonist-bound forms.

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5. dr.umesh on January 24, 2010 1:07 AM writes...

I like the way, u cover the topics and more over I was happy to see your lines...

"it's our ignorance that gives me room for optimism"
(Chemistry World - Column: In the pipeline)

I agree with ur optimism. Though lots of serendipity is adding to the drug discovery, so hoping to see the rapid growth in the field of drug discovery in the days to come....

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6. Jose on January 24, 2010 11:32 PM writes...

Optimism? Really? The fact that so much biologically crucial complexity (suspected but wholly under-appreciated) lurks in a *really* well studied receptor class puts some serious weight behind the "low-hanging fruit" school of thought about the drop off in drug approvals.

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7. smurf on January 25, 2010 1:13 AM writes...

Have not read the paper yet, but key is to proof that the interaction between the receptors is not just an artefact related to the overexpression of the receptors in CHO cells.

Would be interesting to repeat the experiment e.g. with Bladder Smooth Muscle cells.

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