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x-ray crystallography

Looking to Llamas for New Ways to Fight the Flu

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Lllama nanobodiesResearchers are making tremendous strides toward developing better ways to reduce our risk of getting the flu. And one of the latest ideas for foiling the flu—a “gene mist” that could be sprayed into the nose—comes from a most surprising source: llamas.

Like humans and many other creatures, these fuzzy South American relatives of the camel produce immune molecules, called antibodies, in their blood when exposed to viruses and other foreign substances. Researchers speculated that because the llama’s antibodies are so much smaller than human antibodies, they might be easier to use therapeutically in fending off a wide range of flu viruses. This idea is now being leveraged to design a new type of gene therapy that may someday provide humans with broader protection against the flu [1].

MicroED: From Powder to Structure in a Half-Hour

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MicroED determines structure in 30 min

Credit: Adapted from Jones et al.

Over the past few years, there’s been a great deal of excitement about the power of cryo-electron microscopy (cryo-EM) for mapping the structures of large biological molecules like proteins and nucleic acids. Now comes word of another absolutely incredible use of cryo-EM: determining with great ease and exquisite precision the structure of the smaller organic chemical compounds, or “small molecules,” that play such key roles in biological exploration and drug development.

The new advance involves a cryo-EM technique called microcrystal-electron diffraction (MicroED). As detailed in a preprint on [1] and the journal Angewandte Chemie [2], MicroED has enabled researchers to take the powdered form of commercially available small molecules and generate high-resolution data on their chemical structures in less than a half-hour—dramatically faster than with traditional methods!

A Lean, Mean DNA Packaging Machine

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Three views of bacteriophage T4

Credit: Victor Padilla-Sanchez, The Catholic University of America, Washington, D.C.

All plants and animals are susceptible to viral infections. But did you know that’s also true for bacteria? They get nailed by viruses called bacteriophages, and there are thousands of them in nature including this one that resembles a lunar lander: bacteriophage T4 (left panel). It’s a popular model organism that researchers have studied for nearly a century, helping them over the years to learn more about biochemistry, genetics, and molecular biology [1].

The bacteriophage T4 infects the bacterium Escherichia coli, which normally inhabits the gastrointestinal tract of humans. T4’s invasion starts by touching down on the bacterial cell wall and injecting viral DNA through its tube-like tail (purple) into the cell. A DNA “packaging machine” (middle and right panels) between the bacteriophage’s “head” and “tail” (green, yellow, blue spikes) keeps the double-stranded DNA (middle panel, red) at the ready. All the vivid colors you see in the images help to distinguish between the various proteins or protein subunits that make up the intricate structure of the bacteriophage and its DNA packaging machine.

Creative Minds: Preparing for Future Pandemics

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Jonathan Abraham

Jonathan Abraham / Credit: ChieYu Lin

Growing up in Queens, NY, Jonathan Abraham developed a love for books and an interest in infectious diseases. One day Abraham got his hands on a copy of Laurie Garrett’s The Coming Plague, a 1990s bestseller warning of future global pandemics, and he sensed his life’s calling. He would help people around the world survive deadly viral outbreaks, particularly from Ebola, Marburg, and other really bad bugs that cause deadly hemorrhagic fevers.

Abraham, now a physician-scientist at Brigham and Women’s Hospital, Boston, continues to chase that dream. With support from an NIH Director’s 2016 Early Independence Award, Abraham has set out to help design the next generation of treatments to enable more people to survive future outbreaks of viral hemorrhagic fever. His research strategy: find antibodies in the blood of known survivors that helped them overcome their infections. With further study, he hopes to develop purified forms of the antibodies as potentially life-saving treatments for people whose own immune systems may not make them in time. This therapeutic strategy is called passive immunity.

Creative Minds: Complex Solutions to Inflammation

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Hao Wu

Hao Wu

For nearly 20 years, Hao Wu has studied innate immunity, our body’s first line of defense against infection. One of her research specialties is the challenging technique of X-ray crystallography, which she uses to capture the atomic structure of key molecules that drive an inflammatory response. But for this method to work, the proteins have to be coaxed to form regular crystals—and that has often proven to be prohibitively difficult. Wu, now at Boston Children’s Hospital and Harvard Medical School, can be relentless in her attempts to crystallize difficult molecular structures, and this quality has helped her make a number of important discoveries. Among them is the seminal finding that innate immune cells process and internalize signals to handle invading microbes much differently than previously thought.

Innate immune cells, which include macrophages and neutrophils, patrol the body non-specifically, keeping a look out for signs of anything unusual. Using protein receptors displayed on their surfaces, these cells can sense distinctive molecular patterns on microbes, prompting an immediate response at the site of infection.

Wu has shown that these cells form previously unknown protein complexes that mediate the immune response [1, 2]. She received an NIH Director’s 2015 Pioneer Award to help translate her expertise in the structural biology of these signaling complexes into the design of new kinds of anti-inflammatory treatments. This award helps exceptionally creative scientists to pioneer transformative approaches to major challenges in biomedical and behavioral research.

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