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Berkeley Center for Structural Biology to Receive $5M from HHMI to Build a New Microfocus Crystallography Beamline

Friday, October 24th 2014

The Berkeley Center for Structural Biology (BCSB) has operated five beamlines at the Advanced Light Source (ALS) for more than ten years, helping hundreds of crystallographers to determine the structures of more than 1,000 proteins. Two of the BCSB’s beamlines (8.2.1 and 8.2.2) are funded by the Howard Hughes Medical Institute (HHMI) to support the cutting edge research of structural biologists, including those in the HHMI research community. To ensure that these crystallographers have access to state-of-the-art instrumentation and user support, HHMI has pledged $5 million to the BCSB over the next 3 years to construct a new cutting-edge microfocus macromolecular crystallography beamline.

Adams-Ralston-Morton

Paul Adams and Corie Ralston, who worked together to bring in the funding for the GEMINI project, in front of the current HHMI beamlines at the ALS (top). Simon Morton, the scientist who came up with the original idea for GEMINI, prepares to align an x-ray beam (bottom photo).

Working closely with the ALS, the BCSB has developed a plan for GEMINI, a vanguard beamline that provides the structural biology capabilities required by researchers in the coming decade. “GEMINI will have cutting-edge X-ray technology to increase flux and provide a smaller beam focus, as well as advanced automation for sample handling and high performance detectors for data collection,” said Corie Ralston, Head of the BCSB. “HHMI believes, as we do, that this system will be synergistic, exceeding the capability of any currently available structural biology beamline. This kind of project also highlights the interdisciplinary collaborations made possible by the environment at Berkeley Lab. We have access to an extremely talented pool of people with different backgrounds and areas of expertise: Peter Zwart and Simon Morton (Physical Biosciences), Chuck Swenson (Engineering), and Christoph Steier (Accelerator and Fusion Research), to name just a few, who have formed a first-class team working together toward a common goal.”

Hundreds of users access the HHMI beamlines every year, solving high impact challenging problems. One of these discoveries has been made recently by HHMI investigator Jennifer Doudna, Faculty Biochemist in the Physical Biosciences Division, and Professor of Molecular and Cell Biology at UC Berkeley. Doudna used the BCSB beamlines, as well as ALS beamline 8.3.1, to solve the structure of Cas9, lending insight into the CRISPR/Cas9 system. As a result of this increased structural understanding, this bacterial genetic editing system is revolutionizing the field of molecular biology and gaining wide use in a variety of fields.

Some of the most challenging projects in structural biology today involve the study of membrane proteins, receptors, and large protein complexes. While characterizing these systems at a structural level is crucial to understanding their function, these proteins typically yield very small, weakly diffracting crystals. “Progress is being made to study these crystals using free electron lasers, but these are early days for this technology and the experiments are still difficult to perform,” said Paul Adams, Deputy Director of the Physical Biosciences Division and Division Deputy for Biosciences at the Advanced Light Source. Adams is an x-ray crystallographer who has been involved in free electron laser experiments, and he spoke of the opportunity GEMINI provides. “GEMINI helps address the need for solving structures from these challenging systems without resorting to an FEL.”

This transformation of the crystallography experiment is made possible by three major factors. First, development of technology for synchrotron beamlines has resulted in devices that deliver high power “off the shelf” components.

GEMINI brings together the latest technologies in x-ray optics, detectors, and precision sample handlers in one facility.

GEMINI brings together the latest technologies in x-ray optics, detectors, and precision sample handlers in one facility.

The combination of these new technologies with the experience and expertise of the ALS staff means that on-line real-time beam focusing can be realized, so that the spot size and shape can be focused to the exact size of each crystal. Second, GEMINI leverages two robotic sample mounters in a coordinated system that will bring sample exchange times down to seconds, making it home to the world’s fastest sample mounter. Third, technological advances in x-ray detectors now make it possible to collect data sets in minutes or seconds, with better signal-to-noise than the best CCD detectors currently available. Together, these advances will enable centering, rastering, and data collection from every sample within seconds or minutes. With GEMINI, sample exchange and data collection will be so fast that screening and data collection converge. Every crystal – no matter how small or poorly diffracting – can be evaluated and data collected.

The total cost for GEMINI is $10M over a period of three years. Already, the BCSB has secured a commitment of additional funding from industry partners, and several other organizations have expressed their interest. In addition, Berkeley Lab management recognizes the importance of this project to the mission of the Lab, and has committed resources for the infrastructure changes in the ALS ring required to accommodate GEMINI.

GEMINI evolved from the BCSB’s extensive experience with x-ray optics, automation and outstanding operational support. HHMI’s support for this project will help BCSB advance its vision, expertise and service and aid in providing the advanced technologies needed by structural biologists now and in the coming years.

Stimulating Insulin Production in the Fight Against Type-II Diabetes

Tuesday, September 23rd 2014

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.

NIH Funding Boosts Development of New Biophysical Technique

Thursday, June 26th 2014

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 effort, will ultimately enable a better understanding of the dynamics of biological systems at the atomic level.

JCAP Researchers Develop Method to Stabilize Semiconductors for use in Artificial Photosynthesis

Tuesday, June 17th 2014

jcappic2jcappicArtificial 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.

Berkeley Lab Programs Facilitate Blood Cancer Research

Monday, June 2nd 2014

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.