Adult-onset diabetes, characterized by abnormally high blood sugar, affects hundreds of millions of people worldwide.
New treatments for this disease have centered on targeting the human receptor protein GPR40, since it can enhance sugar-dependent insulin secretion.
TAK-875 is a drug developed by the company Takeda to stimulate insulin secretion by binding to this receptor.
However, the structural information needed to fully understand this class of drugs has not been available until now.
In the September 4th issue of Nature, Takeda researchers reported the first three-dimensional structure of this important receptor-drug interaction. The structure was solved at the Advanced Light Source in the Berkeley Center for Structural Biology (Beamline 5.0.3) and reveals details about the mechanism of action of this drug. The results of this study point the way to better and more effective medications for diabetes.
X-ray solution scattering is a routine biophysical technique used to determine structure and dynamics of macromolecules in solution. When solution scattering data is interpreted, often with the aid of known atomic models, an improved understanding of the macromolecule’s biological function and properties emerges. The main challenge associated with solution scattering data is the intrinsic lack of information that can be obtained from such data. By using a technique called fluctuation X-ray scattering (FXS), researchers can significantly enhance the information content of the data. This leads to fewer ambiguities in the resulting structural models and a better understanding of the associated biology. As shown in the figure to the right, fluctuation scattering allows a more detailed reconstruction of the shape of macromolecules in solution as compared to rival techniques.
The technique can be performed at state of the art X-ray facilities, such as the SLAC Linac Coherent Light Source (LCLS), at the ALS and other synchrotron facilities. The current understanding of fluctuation scattering theory, optimal data analyses, and model reconstructing practices is limited, while the availability of user facilities on which these experiments can be performed is growing rapidly. The National Institutes of Health have shown interest in and provided important support for the development of FXS by awarding an R01 grant to Dr. Peter H. Zwart, Biophysicist Research Scientist in the Physical Biosciences Division. The funding, $1.7M USD over the next five years, will be used by Dr. Zwart and his team to develop theory and software for the analyses of FXS data. The research, originating from a Laboratory Directed Research and Development
Artificial photosynthesis is achieved by using light to split water into hydrogen and oxygen. Recently, researchers at the Joint Center for Artificial Photosynthesis (JCAP), utilizing three of the National User Facilities at Berkeley Lab, were able to address one of the major challenges in artificial photosynthesis – the stabilization of semiconductor materials under the harsh conditions required for water splitting. The Physical Biosciences Division’s Ian Sharp led the team that developed and tested this novel method, published recently in the Journal of the American Chemical Society. Utilizing advanced nanofabrication capabilities at the Molecular Foundry, Jinhui Yang of the Material Sciences Division deposited a thin layer of an oxygen evolution catalyst, cobalt oxide, onto silicon electrodes that had been nanotextured for improved stability and efficiency. Cross-sectional transmission electron microscopy was performed at the National Center for Electron Microscopy to visualize the interfaces of the modified semiconductor. Using Beamline 10.3.1 at the Advanced Light Source, scientists employed x-ray absorption near edge spectroscopy to ascertain the chemical composition of the photoelectrode and its changes following operation. This careful characterization helps to establish the success and utility of this approach for improving the performance and stability of silicon electrodes by engineering the catalyst/semiconductor interface. These results open up new possibilities for stabilizing high efficiency semiconductors for solar energy conversion to chemical fuel.
Jay Keasling, Berkeley Lab’s Associate Laboratory Director for Biosciences and the CEO of the Joint BioEnergy Institute (JBEI), has won the 2014 Renewable Energy Prize portion of the prestigious Eni Awards for his achievements in “the microbial production of hydrocarbon fuels.” Sponsored by Eni, a global multibillion dollar energy company headquartered in Rome, the Eni Awards were created to “develop better use of renewable energy, promote environmental research and encourage new generations of researchers.” The Renewable Energy Prize comes with a gold medal and a 200,000 Euros cash award. Keasling, who is also UC Berkeley’s Hubbard Howe Jr. Distinguished Professor of Biochemical Engineering, and a senior faculty scientist with Berkeley Lab’s Physical Biosciences Division, is recognized as a world leader in the burgeoning field of synthetic biology and its applications to the production of clean, green, advanced biofuels.
Cytokines are small proteins, e.g. growth hormone, that induce "signals" inside cells when they bind cell-surface receptors. Many cytokine-induced signals pass through members of the Janus kinase (JAK) family. Mutations in JAK proteins that cause blood cancers were identified a decade ago, but it has not been determined exactly how they do so. Using data collected at the Berkeley Center for Structural Biology at the Advanced Light Source and the Phenix X-ray crystallography software developed in the Physical Biosciences Division for refinement, Genentech’s Charles Eigenbrot and Patrick Lupardus led a team that determined the kinase/pseudokinase structure of JAK family member TYK2. Based on this structural information, they proposed a mechanism for how these mutations could cause blood cancers.
John Kuriyan, Senior Faculty Scientist in the Physical Biosciences Division and Chancellor’s Professor in the Departments of Molecular and Cell Biology and Chemistry at the University of California-Berkeley, gave the inaugural talk of the National Energy Research Super Computing (NERSC) Center’s Nobel Lunchtime Lecture Series.
Kuriyan represented his graduate and post-doctoral mentor, Nobel laureate Martin Karplus. Karplus, along with Michael Levitt and Arieh Warshel, received the Nobel Prize in Chemistry for 2013 for the development of multiscale models for complex chemical systems. In announcing the 2013 Nobel laureates, the Royal Swedish Academy wrote, “Today the computer is just as important a tool for chemists as the test tube. Simulations are so realistic that they predict the outcome of traditional experiments.” Karplus has been using supercomputers at NERSC -- the high-end scientific computing facility for the Department of Energy’s Office of Science -- to support his research since 1998.
In his presentation, “Molecular Dynamics Simulations and the Mechanisms of Protein Complexes,” John Kuriyan used Karplus’ actual slides from his Nobel lecture in Stockholm to introduce the field of molecular dynamics and then gave his perspective as a structural biologist who uses these computational simulations to gain insight into the motions of biomolecules.
Kuriyan’s work includes the X-ray crystal structure of Abl kinase, which is specifically targeted by the drug, Gleevec, used in the treatment of chronic myelogenous leukemia (CML). Molecular dynamics simulations generated in collaboration with David E. Shaw of David E. Shaw Research and Columbia University depict the movement of the inhibitor as it searches for, and eventually finds, the active site.
The work of David Shaw is an example of the power computing plays in the evolution of molecular dynamics. Using Anton, a massively parallel supercomputer designed and built around customized integrated circuits, Shaw has been able to extend the timeframe of molecular dynamics simulations to the more biologically relevant millisecond timescale.
Kuriyan went on to share examples of simulations involving voltage-gated channels when the voltage is flipped, as well as molecular modeling of the replisome assembly at work replicating DNA. Molecular dynamics simulations performed on the sliding clamp at the heart of this machinery have provided insight into its interaction with other molecules in the assembly.
In Karplus’ final comments of his Nobel lecture, he expressed his wish that experimentalists would use these simulations as tools in their research. Kuriyan demonstrated the embodiment of this wish, using computational approaches to inform his research. While Karplus pointed out that like any other method, molecular dynamics simulations have limitations and inherent errors, Kuriyan showed the power of this integrated approach.
Watch this lecture on YouTube.
The U.S. Department of Energy (DOE)’s Joint BioEnergy Institute (JBEI) CEO Jay Keasling announced that Blake Simmons would be stepping into the role of Chief Science and Technology Officer (CSTO). Simmons, who joined JBEI in 2006 as Vice President for one of its divisions, continues to be Senior Manager of the Biofuels & Biomaterials Science and Technology Department at Sandia National Laboratories. JBEI is a multi-institutional partnership led by Lawrence Berkeley National Laboratory.
“We are thrilled that Blake has agreed to take on this new role at JBEI,” said Keasling. “He brings a tremendous amount of multidisciplinary experience in chemical engineering, materials science, and renewable energy to our endeavor. Blake has been a strong leader of our Deconstruction efforts and has catalyzed important breakthroughs. We anticipate that with Blake in this new position, we will significantly advance our mission to produce advanced biofuels.” Simmons takes over from Harvey Blanch, who retired after serving as CSTO since 2007.
As the head of the Deconstruction division, Simmons has been responsible for overseeing the development of more energy-efficient and cost-effective methods to achieve the first step in bioenergy production: deconstructing biomass into fermentable sugars. Under his leadership, researchers have presented various strategies for affecting these goals, including novel methods for identifying microbes that naturally break down biomass within a microbial community, which then become sources for efficient enzyme cocktails that could be used in the biomanufacturing process. In addition, scientists have developed new techniques that do not require the use of expensive enzyme additives for pre-treating biomass and breaking it down into fuel sugars.
Simmons served in the Navy as a Nuclear Propulsion Operator (Electrician’s Mate) for six years. He went on to earn a Bachelor of Science degree from the University of Washington and a PhD from Tulane University, both in Chemical Engineering. He joined Sandia National Laboratories in Livermore, Calif., in 2001 as a member of the Materials Chemistry Department. In 2006, he was promoted to Manager of the Energy Systems department. His expertise includes biomass pretreatment, enzyme engineering, biofuel cells, nanomaterials, microfluidics, desalination, and silica biomineralization.
“In my new role as CSTO, my goal is to accelerate biofuels innovation across JBEI’s entire collaborative network, while ensuring that our research and development efforts align with industry needs and standards,” said Simmons. “With my colleagues, I look forward to creating an atmosphere that enables technical innovations that will lead to exciting technology transfer and business development opportunities.”
Contact information: Lida Gifford, (510) 495-2563, email@example.com. For more about JBEI, visit their website.
# # #JBEI is one of three Bioenergy Research Centers established by the DOE’s Office of Science in 2007. It is a scientific partnership led by Berkeley Lab and includes the Sandia National Laboratories, the University of California campuses of Berkeley and Davis, the Carnegie Institution for Science, and the Lawrence Livermore National Laboratory. DOE’s Bioenergy Research Centers support multidisciplinary, multi-institutional research teams pursuing the fundamental scientific breakthroughs needed to make production of cellulosic biofuels, or biofuels from nonfood plant fiber, cost-effective on a national scale.
The Ebola virus outbreak in West Africa has claimed over 110 lives and more than 170 suspected or confirmed cases have been reported. While there is no known cure, basic research is providing insight into the action of the virus. Zachary Bornholdt and Erica Ollman Saphire from The Scripps Research Institute spearheaded a team of researchers from the University of Wisconsin-Madison, University of Tokyo, and the Japan Science and Technology Agency, studying an Ebola virus protein. The Ebola virus genome encodes for 8 proteins, one of which is VP40, a multifunctional protein with critical roles at different stages of the virus life cycle. To elucidate the VP40 structure and its related function, they crystallized the protein and collected data at three light sources, including the Berkeley Center for Structural Biology (Beamline 5.0.2) at the Advanced Light Source. The researchers analyzed the X-ray data using PHENIX, automated crystallography software for determining macromolecular structure, developed under the direction of Paul Adams in the Physical Biosciences Division.
In a study published in Cell, Bornholdt and colleagues report that VP40 has three different conformations: a dimer, hexamer, and octamer (pictured; Bornholdt, et al., 2013). Further studies of these multiple forms indicate that this viral protein assumes different conformations depending on the function being performed. When a dimer, VP40 interacts with other VP40 dimers to form a linear filament that is essential for building the shell of the virus. Through electrostatic interaction and conformational changes, the dimer rearranges into a hexamer responsible for building and budding Ebola virus virions. As an eight-member ring, assembled from four dimers, VP40 binds RNA, the genetic material of the Ebola virus, and acts to control viral transcription in infected cells.
Much like the multi-functional protein itself, these results accomplish more than one goal. First, this work provides evidence to support the theory that the proteins of other viruses may be performing multiple functions. Second, these findings reinforce the desirability of VP40 as a target for anti-Ebola virus drugs. The structure-shifting nature of this protein allows for either targeting by more than one drug or upsetting the balance of the different protein conformations, thereby impeding the viral life cycle. Regardless of the approach taken, this work highlights areas that can be exploited to decrease the virulence of this deadly Ebola virus.
Presented by R&D Magazine, the R&D 100 Awards recognize the year’s top 100 technology products from industry, academia, and government-sponsored research, ranging from chemistry to materials to biomedical breakthroughs. The eight awards this year mark a record high for Berkeley Lab and brings the total of Berkeley Lab’s R&D 100 wins to 70, plus two Editors’ Choice Awards. In all, Department of Energy’s national laboratories and facilities won 36 R&D 100 Awards this year.
The Bacteriophage Power Generator generates power using harmless viruses that convert mechanical energy into electricity, providing a sustainable, cost-effective, nontoxic energy source capable of powering electronics and microdevices. It is unique in addressing the energy challenge of predominantly battery-driven devices. Developed by Seung-Wuk Lee (pictured) working with Ramamoorthy Ramesh and Byung Yang Lee, all Berkeley Lab scientists, this generator is the first to produce electricity by harnessing the piezoelectric properties of a biological material.
Because the energy-generating virus infects only bacteria, it is not harmful to humans and is biocompatible and nontoxic, unlike conventional piezoelectric materials such as lead, cadmium, and lithium. This opens the door to applications in biomedical devices, particularly those to be implanted into the human body. This invention is also a breakthrough in the concept of nanomanufacturing, as it exploits the unique natural ability of a virus to synthesize materials that can self-assemble and selfreplicate.
Researchers at the Joint BioEnergy Institute (JBEI), led byTrent Northen (pictured) , a staff scientist at JBEI and Berkeley Lab’s Life Sciences Division, have developed a high-throughput screening tool to support the development of lignocellulosic biofuels. High-Throughput Nanostructure-Initiator Mass Spectrometry (HT-NIMS) is a high-speed chemical screening system that can precisely determine the molecular composition of thousands of samples arrayed on a small slide of silicon at speeds 100 times faster than conventional methods.
HT-NIMS makes novel use of miniaturization, lasers, specialized chemistries, and robotics. In addition to the biofuels applications, the technology can also be used for a host of biological, bio-industrial, and medical uses, including discovering new drug prospects, cancer diagnostics, and clinical testing. Co-inventors with Northen were Berkeley Lab scientist Xiaoliang Cheng and San Diego, Calif.-based Nextval Inc.
Peter Zwart's group at the Advanced Light Source (ALS), Beamline 5.0.2, a protein crystallography beamline that is part of the Berkeley Center for Structural Biology (BCSB), became the second ALS beamline to reach the 1,000 published structures mark. Proteins are the workhorses of biology, responsible for much of the architecture and chemistry of living cells. Knowing the crystal structure of a protein is the key to determining its function. The 1,000th published protein structure at 5.0.2 was a thiourea-containing anti-cancer agent. Beamline 8.3.1 became the first ALS beamline to pass the 1,000 published structure milestone earlier this year.
Dr. Naomi Ginsberg, an assistant professor of Chemistry and Physics at UC Berkeley, has joined PBD as a Faculty Scientist. Ginsberg received her B. A. Sc in Engineering Science from the University of Toronto in 2000 and earned a Ph.D. in Physics from Harvard in 2007. She was a Glenn T. Seaborg Postdoctoral Fellow at the Lab from 2007 through 2010, working with the Fleming group. She received the DARPA Young Faculty Award in 2012 and was a Packard Fellow for Science and Engineering in 2011. She was also the Cupola Era Endowed Chair in the College of Chemistry from 2010-2012.
Ginsberg’s research emphasis includes physical and biophysical chemistry as well as light harvesting, spectroscopy, and imaging. Her group focuses on visualizing ultrafast energy flow in natural and artificial light harvesting systems and on combining electron and optical microscopies to facilitate high-resolution studies of living things and molecular interactions in solution.
The Ginsberg group uses multiple approaches, separately and in combination, including ultrafast spectroscopy, light microscopy, and cathodoluminescence electron microscopy. A common theme is to deeply understand the nature of the light-matter interactions being used in order to optimally measure these complex dynamics..
Current projects aim to (1) map spatio-temporal photoexcitation trajectories onto the architecture of natural and artificial photosynthetic light harvesters by adapting fluorescence microscopy to time-resolve ultrafast energy flow, and (2) to develop near-field optical microscopies by leveraging the high spatial resolution of electron optics and the spectral selectivity of cathodoluminescence in order to study photosynthetic membrane reorganization under physiological conditions.
To learn how biological molecules like proteins function, scientists must first understand their structures. Almost as important is understanding how the structures change, as molecules in the native state do their jobs.
Existing methods for solving structure largely depend on crystallized molecules, and the shapes of more than 80,000 proteins in a static state have been solved this way. The majority of the two million proteins in the human body can’t be crystallized, however. For most of them, even their low-resolution structures are still unknown.
Their chance to shine may have come at last, thanks to new techniques developed by Peter Zwart and his colleagues at the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab), working with collaborators from Arizona State University, the University of Wisconsin-Milwaukee, and DOE’s Pacific Northwest National Laboratory (PNNL). The new method promises a more informative look at large biological molecules in their native, more fluid state.
The researchers describe their results in two recent papers in Foundations of Crystallography and in Physical Review Letters.
Doug Clark of the Physical Biosciences Division has been named the dean of UC Berkeley’s College of Chemistry. Clark is a pioneering researcher in the field of biochemical engineering, with particular emphasis on enzyme technology, biomaterials, extremophiles and all areas of biofuels research. Clark will begin his new responsibilities, pending formal approval of his appointment from the UC Regents, on July 1. He will succeed Richard Mathies — also with the Physical Biosciences Division — who has served as dean for five years.
Says Clark, “It is a tremendous honor to be chosen to lead the College of Chemistry, with its rich tradition of path-breaking research and teaching. I look forward to building on the great work of outgoing dean Rich Mathies, who has led the college during a difficult time and who is now handing over the keys to a smoothly running machine. With the support of my colleagues, staff members and students, and our many alumni and friends, I plan to continue to steer the college forward into the future.”
Heinze Frei is the lead scientist of the part of the center that's affiliated with the Lawrence Berkeley National Laboratory. JCAP is a joint venture with Caltech. And at the moment, the Berkeley labs are spread out in an open room that feels like a squeaky clean warehouse.
Frei explains that the concept is to use sunlight as an energy source to take carbon dioxide from the air and turn it into fuel. That's exactly what green plants do.
"It's like an artificial leaf but spread over very large areas," he says. You would need a forest's worth of such leaves to make a meaningful amount of fuel.
Frei says it's not simply a matter of proving the concept of artificial photosynthesis — that was done a decade ago. The challenge now is to drive down the cost, using cheap materials and increasing the efficiency.