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Gray Wins Prestigious Medal for Achievements in Chemistry

Harry Gray, the Arnold O. Beckman Professor of Chemistry and the founding director of the Beckman Institute, has been awarded the Theodore William Richards Medal for "conspicuous achievement in chemistry." The award is the oldest and most prestigious award of the Northeastern Section of the American Chemical Society (NESACS). It is named in honor of the first U.S. Nobel laureate in Chemistry.

Over the past 20 years, Gray's research on electron-transfer chemistry has spanned across inorganic chemistry, biochemistry, and biophysics. Electron transfer, the fundamental process by which atoms trade electrons, is ubiquitous in both natural and artificial systems from photosynthesis to photography. While this process is a cornerstone for much of chemistry, its mechanisms can be complex. Researchers in the Gray group measure rates of electron exchange within diverse metals and proteins, and have accelerated those rates for certain compounds that naturally transfer electrons very slowly.

Gray is also the director for the Center for Chemical Innovation (CCI Solar), which aims to create a clean, storable fuel from sunlight using artificial photosynthesis. Artificial photosynthesis requires a catalyst to absorb solar energy to split water into hydrogen fuel and oxygen. Traditional catalysts for this artificial process, like platinum, tend to be expensive and scarce. Gray's group is hunting for a mixture of simple, inexpensive, and abundant metal-oxide catalysts that can mimic the complex mechanisms of photosynthesis that occur in nature.

Gray has received numerous awards and honors, including the National Medal of Science in 1986 and the California Scientist of the Year in 1988. He is a member of the National Academy of Sciences and a fellow of the American Academy of Arts and Sciences. He has also published 17 books and more than 730 research papers.

Gray will receive the Richards Medal at the NESACS meeting on March 5, 2015, where he will give an award address titled "Solar-Driven Water Splitting."

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Monday, April 20, 2015
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Stoltz Wins Grant from the Camille and Henry Dreyfus Foundation

Professor of Chemistry Brian Stoltz has been awarded a $120,000 grant from the Camille and Henry Dreyfus Foundation's Postdoctoral Program in Environmental Chemistry. The grant, distributed over two years, provides funds for a principal investigator to appoint a postdoctoral fellow to work on "innovative fundamental research in the chemical sciences or engineering related to the environment."

Stoltz's lab focuses on using chemical synthesis to develop new reactions and strategies for manufacturing complex molecules. In collaboration with the laboratories of Paul Wennberg, the R. Stanton Avery Professor of Atmospheric Chemistry and Environmental Science and Engineering, and Mitchio Okumura, professor of chemical physics, Stoltz's group will use the Dreyfus Foundation grant to fund a postdoctoral scholar and an interdisciplinary project that merges the fields of synthetic, organic, and environmental reaction chemistry.

"We plan to employ organic synthesis as a tool to help address unresolved questions that have eluded traditional methods of experimental atmospheric chemistry, including the identification of oxidation mechanisms that lead to the formation of organic particulate matter and to the regeneration of atmospheric oxidant radicals," says Stoltz. "In the process, we hope to educate a postdoctoral scholar and expose them to a broad range of scientific disciplines and skills by applying techniques from synthetic and atmospheric chemistry in an interdisciplinary setting."

Fourteen other Caltech professors have received this grant since its inception in 1996.

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Monday, March 2, 2015
Winnett Lounge

The Secret Life of a Snowflake

Caltech Biochemist Sheds Light on Structure of Key Cellular 'Gatekeeper'

Facing a challenge akin to solving a 1,000-piece jigsaw puzzle while blindfolded—and without touching the pieces—many structural biochemists thought it would be impossible to determine the atomic structure of a massive cellular machine called the nuclear pore complex (NPC), which is vital for cell survival.

But after 10 years of attacking the problem, a team led by André Hoelz, assistant professor of chemistry, recently solved almost a third of the puzzle. The approach his team developed to do so also promises to speed completion of the remainder.

In an article published online February 12 by Science Express, Hoelz and his colleagues describe the structure of a significant portion of the NPC, which is made up of many copies of about 34 different proteins, perhaps 1,000 proteins in all and a total of 10 million atoms. In eukaryotic cells (those with a membrane-bound nucleus), the NPC forms a transport channel in the nuclear membrane. The NPC serves as a gatekeeper, essentially deciding which proteins and other molecules are permitted to pass into and out of the nucleus. The survival of cells is dependent upon the accuracy of these decisions.

Understanding the structure of the NPC could lead to new classes of cancer drugs as well as antiviral medicines. "The NPC is a huge target of viruses," Hoelz says. Indeed, pathogens such as HIV and Ebola subvert the NPC as a way to take control of cells, rendering them incapable of functioning normally. Figuring out just how the NPC works might enable the design of new drugs to block such intruders.

"This is an incredibly important structure to study," he says, "but because it is so large and complex, people thought it was crazy to work on it. But 10 years ago, we hypothesized that we could solve the atomic structure with a divide-and-conquer approach—basically breaking the task into manageable parts—and we've shown that for a major section of the NPC, this actually worked."

To map the structure of the NPC, Hoelz relied primarily on X-ray crystallography, which involves shining X-rays on a crystallized sample and using detectors to analyze the pattern of rays reflected off the atoms in the crystal.

It is particularly challenging to obtain X-ray diffraction images of the intact NPC for several reasons, including that the NPC is both enormous (about 30 times larger than the ribosome, a large cellular component whose structure wasn't solved until the year 2000) and complex (with as many as 1,000 individual pieces, each composed of several smaller sections). In addition, the NPC is flexible, with many moving parts, making it difficult to capture in individual snapshots at the atomic level, as X-ray crystallography aims to do. Finally, despite being enormous compared to other cellular components, the NPC is still vanishingly small (only 120 nanometers wide, or about 1/900th the thickness of a dollar bill), and its highly flexible nature prohibits structure determination with current X-ray crystallography methods.

To overcome those obstacles, Hoelz and his team chose to determine the structure of the coat nucleoporin complex (CNC)—one of the two main complexes that make up the NPC—rather than tackling the whole structure at once (in total the NPC is composed of six subcomplexes, two major ones and four smaller ones, see illustration). He enlisted the support of study coauthor Anthony Kossiakoff of the University of Chicago, who helped to develop the engineered antibodies needed to essentially "superglue" the samples into place to form an ordered crystalline lattice so they could be properly imaged. The X-ray diffraction data used for structure determination was collected at the General Medical Sciences and National Cancer Institutes Structural Biology Beamline at the Argonne National Laboratory.

With the help of Caltech's Molecular Observatory—a facility, developed with support from the Gordon and Betty Moore Foundation, that includes a completely automated X-ray beamline at the Stanford Synchrotron Radiation Laboratory that can be controlled remotely from Caltech—Hoelz's team refined the antibody adhesives required to generate the best crystalline samples. This process alone took two years to get exactly right.

Hoelz and his team were able to determine the precise size, shape, and the position of all atoms of the CNC, and also its location within the entire NPC.

The CNC is not the first component of the NPC to be fully characterized, but it is by far the largest. Hoelz says that once the other major component—known as the adaptor–channel nucleoporin complex—and the four smaller subcomplexes are mapped, the NPC's structure will be fully understood.

The CNC that Hoelz and his team evaluated comes from baker's yeast—a commonly used research organism—but the CNC structure is the right size and shape to dock with the NPC of a human cell. "It fits inside like a hand in a glove," Hoelz says. "That's significant because it is a very strong indication that the architecture of the NPC in both are probably the same and that the machinery is so important that evolution has not changed it in a billion years."

Being able to successfully determine the structure of the CNC makes mapping the remainder of the NPC an easier proposition. "It's like climbing Mount Everest. Knowing you can do it lowers the bar, so you know you can now climb K2 and all these other mountains," says Hoelz, who is convinced that the entire NPC will be characterized soon. "It will happen. I don't know if it will be in five or 10 or 20 years, but I'm sure it will happen in my lifetime. We will have an atomic model of the entire nuclear pore."

Still, he adds, "My dream actually goes much farther. I don't really want to have a static image of the pore. What I really would like—and this is where people look at me with a bit of a smile on their face, like they're laughing a little bit—is to get an image of how the pore is moving, how the machine actually works. The pore is not a static hole, it can open up like the iris of a camera to let something through that's much bigger. How does it do it?"

To understand that machine in motion, he adds, "you don't just need one snapshot, you need multiple snapshots. But once you have one, you can infer the other ones much quicker, so that's the ultimate goal. That's the dream."

Along with Hoelz, additional Caltech authors on the paper, "Architecture of the Nuclear Pore Complex Coat," include postdoctoral scholars Tobias Stuwe and Ana R. Correia, and graduate student Daniel H. Lin. Coauthors from the University of Chicago Department of Biochemistry and Molecular Biology include Anthony Kossiakoff, Marcin Paduch and Vincent Lu. The work was supported by Caltech startup funds, the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, the 54th Mallinckrodt Scholar Award of the Edward Mallinckrodt, Jr. Foundation, and a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research.

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Chemists Solve Key Cellular Puzzle
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Chemists Solve Key Cellular Puzzle
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