Creative Minds: Breaking Size Barriers in Cryo-Electron Microscopy

Dmitry Lyumkis

Dmitry Lyumkis

When Dmitry Lyumkis headed off to graduate school at The Scripps Research Institute, La Jolla, CA, he had thoughts of becoming a synthetic chemist. But he soon found his calling in a nearby lab that imaged proteins using a technique known as single-particle cryo-electron microscopy (EM). Lyumkis was amazed that the team could take a purified protein, flash-freeze it in liquid nitrogen, and then fire electrons at the protein, capturing the resulting image with a special camera. Also amazing was the sophisticated computer software that analyzed the raw 2D camera images, merging the data and reconstructing it into 3D representations of the protein.

The work was profoundly complex, but Lyumkis thrives on solving extremely difficult puzzles. He joined the Scripps lab to become a structural biologist and a few years later used single-particle cryo-EM to help determine the atomic structure of a key protein on the surface of the human immunodeficiency virus (HIV), the cause of AIDS. The protein had been considered one of the greatest challenges in structural biology and a critical target in developing an AIDS vaccine [1].

Now, Lyumkis has plans to take single-particle cryo-EM to a whole new level—literally. He wants to develop new methods that allow it to model the atomic structures of much smaller proteins. Right now, single-particle cryo-EM has worked with proteins as small as roughly 150 kilodaltons, a measure of a protein’s molecular weight (the approximate average mass of a protein is 53 kDa). Lyumkis plans to drop that number well below 100 kDa, noting that if his new methods work as he hopes, there should be very little, if any, lower size limit to get the technique to work. He envisions generating within a matter of days or weeks the precise structure of an average-sized protein involved in a disease, and then potentially handing it off as an atomic model for drug developers to target for more effective treatment.

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Snapshots of Life: New Target for Herpes Treatment?


HSV-1Something about this image reminds me of that wacky and infectious old song: “It was a one-eyed, one-horned, flyin’ purple people eater …” Of course, this purple blob isn’t a people eater, but it does happen to be infectious. What you see here is a 3D rendering of a protein that the herpes simplex virus 1 (HSV-1)—one of two herpes viruses that cause genital herpes and cold sores—depends upon to infect human cells.

When a cell is infected with HSV-1, the virus inserts its DNA into human cells, periodically coming out of dormancy to make more copies of itself. However, errors sometimes occur when the DNA is replicated. When that happens, an HSV-1 protein, dubbed infected cell protein 8 (ICP8), stitches broken pieces of DNA back together. That’s what you see depicted in this schematic, which shows two single strands of DNA (red with multicolor bases) entering an ICP8 complex (purplish blue) to be reannealed into DNA’s familiar double-stranded helix (red).

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