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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

« Science Gifts: Actual Med-Chem Books | Main | Fluorous Technologies Is No More »

December 3, 2012

Stanford's Free Electron Laser Blasts Away

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Posted by Derek

Here's another next-generation X-ray crystal paper, this time using a free electron laser X-ray source. That's powerful enough to cause very fast and significant radiation damage to any crystals you put in its way, so the team used a flow system, with a stream of small crystals of T. brucei cathepsin B enzyme being exposed in random orientations to very short pulses of extremely intense X-rays. (Here's an earlier paper where the same team used this technique to obtain a structure of the Photosystem I complex). Note that this was done at room temperature, instead of cryogenically. The other key feature is that the crystals were actually those formed inside Sf9 insect cells via baculovirus overexpression, not purified protein that was then crystallized in vitro.

Nearly 4 million of these snapshots were obtained, with almost 300,000 of them showing diffraction. 60% of these were used to refine the structure, which out at 2.1 Angstroms, and clearly showed many useful features of the enzyme. (Like others in its class, it starts out inhibited by a propeptide, which is later cleaved - that's one of the things that makes it a challenge to get an X-ray structure by traditional means).

I'm always happy to see bizarre new techniques used to generate X-ray structures. Although I'm well aware of their limitations, such structures are still tremendous opportunities to learn about protein functions and how our small molecules interact with them. I wrote about the instrument used in these papers here, before it came on line, and it's good to see data coming out of it.

Comments (7) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News


COMMENTS

1. Boghog on December 3, 2012 11:06 AM writes...

also known as "diffraction before destruction"

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2. Brooks Moses on December 4, 2012 1:29 AM writes...

Boghog @1: In this case, rather like "pillage, _then_ burn".

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3. Vanzetti on December 4, 2012 7:54 AM writes...

Ah, X-ray laser, also known as The Death Ray. Soon in an airborne cannon form?

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4. metaphysician on December 4, 2012 5:38 PM writes...

Is the apparatus in question an actual x-ray laser? Or merely(?) an x-ray source that uses a laser to generate the rays?

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5. Paul on December 4, 2012 8:09 PM writes...

#4: it uses high energy electrons from the Stanford Linear Accelerator Center to produce a very short pulse of coherent X-rays. It's an x-ray frequency free electron laser.

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6. jbosch on December 5, 2012 10:14 PM writes...

And it is an extremely powerful technique. In particular if one fails to produce useful crystals suitable for normal x-ray diffraction. The method seems to mature fairly quickly, however there are only very few facilities with these capabilities. I think the one in Hamburg will be completed in 2016 if I'm not wrong.
Follow the link to a very good paper about the method:
http://www.ncbi.nlm.nih.gov/pubmed/21293373

Permalink to Comment

7. jbosch on December 5, 2012 10:18 PM writes...

and this link for an overview:
http://www.ncbi.nlm.nih.gov/pubmed/22922042

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