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Getting a glimpse of the shape molecules actually take in the cell

Getting a glimpse of the shape molecules actually take in the cell

Working at a medical school, every day I talk to scientists who are discovering ever more intricately detailed information about our bodies and our cells. With these daily amazements about what we do know, it’s always good to be reminded of how much is still unknown.

Case in point, I recently talked with Xuesong Shi, PhD, a postdoctoral fellow in the lab of biochemist Dan Herschlag, PhD. He has been trying to understand the many configurations and structures molecules and complexes of molecules take on. This may seem a bit abstract, but what the molecules look like – how many different shapes they fold into and how they interact with each other – can provide information that explains both how molecules behave normally, and also why they fail to work properly in some diseases.

For a long time now most of the information we have about the shape and structure of molecules came from turning those molecules into crystals of rigidly packed, identical structures. That’s a technique called X-ray crystallography, which people at Stanford carry out using the powerful X-ray beams at SLAC.

Herschlag points out that X-ray crystallography has been extremely valuable for helping scientists understand the molecules that make up our cells. But the crystals don’t necessarily give the whole picture. For example, molecules are thought to take on many different shapes when forming complexes, not just the single shaped found in a crystal. “The idea is that molecules have many forms in solution,” Shi said. Some molecules also don’t form crystals well.

Shi has been tackling this problem using an X-ray interferometry technique developed in the lab of biochemist Pehr Harbury, PhD, who collaborated with Herschlag and Shi on the work. It involves attaching tiny gold particles to known locations on molecules – in this case a snippet of DNA. Then, by using X-rays to look at where the gold particles are in relation to each other, scientists can piece together the myriad shapes the molecules take on when freed from a crystal lattice.

Shi was first author on a paper published online March 31 in the Proceedings of the National Academy of Sciences describing this technique. He told me that although that paper investigated the structure of DNA, he hopes to use the technique to better understand a variety of molecules where knowing the myriad shapes the molecule takes on is essential for understanding its function.

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