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SSRL Headlines Vol. 9, No. 10  April, 2009


Contents of this Issue:

  1. User Safety Update
  2. Caution Advised Regarding Swine Flu Outbreak
  3. Science Highlight — Novel Mechanism for DNA Biosynthesis in Organisms with Gene thyX could Lead to Better Antibiotics
  4. Science Highlight — Finding the Crystal Structure of P-gp: A Protein that Makes Cancer Cells Resistant to Chemotherapy
  5. Science Highlight — A New Way to Limit Damaging Production of Nitric Oxide
  6. From the Director of the Stanford Synchrotron Radiation Lightsource: Timeless SSRL
  7. First Light Achieved on Beam Line 14-1
  8. SSRL X-ray/VUV Proposals due June 1
  9. Photon Science Faculty Members Awarded Endowed Chairs
  10. New Era of Research Begins as World's First Hard X-ray Laser Achieves "First Light"
  11. LCLS User Research Administration Update
  12. LCLS Proposals for AMO and SXR Instruments due May 15, 2009
  13. Photon Science-Related Workshops, Conferences and Schools

1.   User Safety Update
       (contacts: J. Stohr,; B. Bozorg-Chami,; M. Padilla,

We take very seriously the challenges of safety at SSRL. We want to remind everyone who uses SSRL facilities that you share in the responsibility of ensuring a safe workplace. That includes planning experiments properly, taking extra efforts in identifying related hazards, and working closely with us to develop mitigations and controls.

We recently issued a user safety advisory regarding an injury caused when a glass, crimp-top vial used to transport air sensitive solutions under liquid nitrogen burst while it was being warmed to room temperature. This incident identified a significant safety issue with these types of sample containers. This incident is currently being investigated; the results and lessons learned will be shared shortly.

As a final note, immediately report any unsafe work practices or safety concerns to the SSRL Duty Operator, Safety Officers and/or staff to continue to make SSRL a safe workplace.

Behzad Bozorg-Chami
SSRL ES&H Coordinator:
Matthew Padilla

2.   Caution Advised Regarding Swine Flu Outbreak

The World Health Organization and U.S. Centers for Disease Control have reported 40 confirmed cases of swine flu in the U.S. with no fatalities. Most cases occurred in New York, all within one school. As of yesterday, seven had been reported in Southern California, with one in Northern California (Sacramento). No Stanford faculty, staff or students had reported symptoms of concern. Stanford officials are advising students, faculty and staff to avoid travel to Mexico.

As a precaution in case the flu should spread in the United States, Secretary of Homeland Security Janet Napolitano declared a public health emergency to allow the release of funds in case a public health response is needed. Influenza is thought to spread mainly person-to-person through coughing or sneezing of infected people.

The CDC provides some simple tips for staying healthy during any flu season:

  • Cover your nose and mouth with a tissue when you cough or sneeze. Throw the tissue in the trash after you use it.
  • Wash your hands often with soap and hot water, especially after you cough or sneeze. Alcohol-based hands cleaners may also be effective
  • Avoid touching your eyes, nose or mouth. The virus spreads that way.
  • Try to avoid close contact with sick people.
  • If you feel unwell, stay home from work or school and limit contact with others to keep from infecting them.
Stanford University is closely monitoring developments in the international outbreak of Swine Influenza. For information and updates see "Information About Pandemic Influenza".

See also the university's Emergency Information page. Additional recommendations and information are available on the World Health Organization and U.S. Centers for Disease Control Web sites.

At SLAC you can also contact SLAC Medical at ext. 2281.

3.  Science Highlight — Novel Mechanism for DNA Biosynthesis in Organisms with Gene thyX could Lead to Better Antibiotics
       (contacts: I. Mathews,; A. Kohen,

highlight figure
Before DNA is made, the subunits composing DNA must be made. The essential process of making one of these subunits, thymidine monophosphate (TMP), was thought to be similar for most living things, but scientists recently discovered that some bacteria and viruses use a different type of enzyme to perform this reaction. The discovery might result in new antibiotics that would be effective against human pathogens, but not affect human cells.

The research group led by Prof. Amnon Kohen of the University of Iowa analyzed the reactions of the enzyme called flavin-dependent thymidylate synthase (FDTS), used by some pathogenic bacteria, to turn dexoyuridine monophosphate (dUMP) into TMP. The mechanism they propose is not only different than the mechanism used by thymidylate synthase in eukaryotes including humans, it also has novel properties that had not previously been seen in biological systems.

The proposed mechanism is based on chemical and structural analysis of the FDTS enzyme. Kohen's group performed crucial chemical analysis of the enzyme and reaction, including labeled isotopic substitution and a form of mass spectrometry. To determine the molecular structure, Kohen's group provided purified material to Irimpan Mathews of SSRL, who crystallized and solved the structures of selected mutant FDTS enzymes. Structural data provided a detailed description of the active site of the enzyme. They collected x-ray diffraction data at SSRL's Beam Line 9-2.

Drugs designed to target the FDTS enzyme could provide treatments for various diseases including anthrax, tuberculosis, botulism, syphilis, pneumonia, and Lyme disease. Multiple drug resistant bacteria are likely to be susceptible to such agents, since the antibiotics currently in use do not target FDTS. This work was published in the April 16 issue of Nature.

To learn more about this research see the full scientific highlight at:

4.  Science Highlight — Finding the Crystal Structure of P-gp: A Protein that Makes Cancer Cells Resistant to Chemotherapy
       (contact: G. Chang,

highlight figure
Medications can be rendered ineffective through cells developing multidrug resistance. This is the case in many forms of cancer cells that fail to respond to chemotherapy. The ability of these cells to avoid the effects of drugs can be due to the actions of P-glycoprotein (P-gp). This protein sits in the membranes of cells and acts like a pump. It ushers a wide range of potentially harmful molecules from inside the membrane to outside the cell. Unfortunately, it can also mediate the removal of life-saving medications.

The mechanism behind the ability of P-gp to act upon such a diverse range of chemicals has been a mystery. The recent crystal structure of P-gp sheds light on its mechanism and brings scientists a step closer to developing ways to prevent P-gp from banishing medicines from cells.

A research team led by Prof. Geoffrey Chang of The Scripps Research Institute used SSRL Beam Lines 9-2 and 11-1 to collect part of the x-ray diffraction data used to solve the structure of mouse P-gp. In the crystal, the protein looks like a "V" with bulbous ends. The scientists believe that they caught P-gp in the pre-transport state, where the protein is ready to bind a target molecule. The open arms of the "V" extend through the membrane into the cytoplasm and the closed point of the "V" extends outside the cell.

P-gp likely works by binding a molecule in a central cavity and closing its open arms to create a cage. It then opens the other ends of the arms to reverse the "V", depositing the trapped molecule outside the cell. While both the bacterial and the mouse versions of the molecule have many hydrophobic side-chains lining their cavities, the mouse P-gp has many more aromatics. These sticky residues could bind to a variety of organic molecules, which may explain P-gp's ability to target a wide range of molecules.

Understanding how medicinal molecules bind to P-gp will enable researchers to redesign existing drugs to avoid falling into this trap and thus be more likely to retain their potency. This work was published in the March 27 issue of the journal Science.

To learn more about this research see the full scientific highlight at:

5.  Science Highlight — A New Way to Limit Damaging Production of Nitric Oxide
       (contacts: E. Garcin,; E.D. Getzoff,

highlight figure
Nitric oxide (NO) is one of very few gaseous signaling molecules in humans. NO causes smooth muscles to relax and blood vessels to open. Its deficiency leads to disorders such as hypertension and impotence, but too much NO can lead to rheumatoid arthritis, stroke, cancer, and other diseases. Three distinct but related enzymes (called nitric oxide synthases) make NO from an arginine molecule. One of the nitric oxide synthases, iNOS, creates localized, high concentrations of NO as part of the body's immune response. Because it is this elevated activity of iNOS that can cause disease, scientists would like to specifically inhibit the action of iNOS without interfering with the activity of the other two enzymes, eNOS and nNOS. Since the three enzymes have identical active sites (i.e. where NO is made), finding an inhibitor that will bind in this site for iNOS but not eNOS nor nNOS has proved challenging.

Crystal structures by a research group led by Prof. Elizabeth Getzoff of The Scripps Research Institute have revealed a mechanism that allows selective inhibition of iNOS. Using data partially collected at SSRL Beam Lines 7-1, 9-1, and 9-2, the group solved 17 structures of NOS enzymes bound to a variety of inhibitors.

Some of the inhibitors, as seen in the crystal structures, had a surprising effect on iNOS. These inhibitors bound loosely in the arginine binding area of the enzyme's active site and caused a chain reaction of structural changes. This resulted in an additional binding site opening far away from the active site. Only those inhibitor molecules that have a tail that could reach and bind in this additional site effectively inhibited iNOS but not eNOS. While the inhibitors could similarly bind at the active sites, the eNOS enzyme did not open an additional binding site for the inhibitors' tail.

Uncovering this new binding mechanism informs the future design of drugs that specifically inhibit iNOS activity. Inhibitors can have a region that binds loosely in the active site and a tail that swings around to bind in a distant, and distinct, secondary site created by the active site interactions. The researchers have called this an anchored plasticity approach and suggest that it may be useful for designing selective inhibitors for other enzymes that are difficult to target due to their similarities to other enzymes. This work was published in the November 2008 issue of Nature Chemical Biology.

To learn more about this research see the full scientific highlight at:

6.   From the Director of the Stanford Synchrotron Radiation Lightsource: Timeless SSRL
       April 3, 2009 SLAC Today Article by Jo Stöhr

J. Stohr
In my last SLAC Today column, I wrote about the history of the Stanford Synchrotron Radiation Laboratory and how it fits into the bigger model of "one lab." In the meantime, SSRL changed its name from "Laboratory," which now appears in the SLAC name, to the more appropriate "Lightsource." Today I want to update you on how this 35-plus-year-old lightsource manages to keep up with the best in the world. No doubt, SSRL has stiff competition: the Web site now lists nearly 70 lightsources worldwide. Here is the story of how through the years SSRL has kept its place in the elite club of facilities that can count themselves as "top notch" in terms of brilliant x-rays, number of users and scientific achievements.

In terms of spectral brightness, a metric that best characterizes the quality of an x-ray source, SSRL's SPEAR3 is an excellent source; yet newer ones just commissioned or under construction have edged ahead with time. Fortunately, however, source brightness is only part of the story in lightsource quality. Given that the performance of our source is sufficiently close to the best, other factors can move us ahead on the path to scientific excellence. The secret of SSRL's success has been to squeeze the most out of what is there. Tight operations budgets and understaffing, especially over the last two years, have been overcome by the ability of SSRL staff to tighten their belts, stretch their responsibilities and go the extra mile in support of the user program. Another factor is the quality of the SSRL scientific staff, which always receives special mention during external reviews. Many of our scientists carry out their own scientific programs, performing experiments not only at SSRL but if needed also at other synchrotron radiation facilities. In the end, they bring back to SSRL what they have seen and learned, and this is incorporated into the SSRL program. Read more in the full SLAC Today article.

7.   First Light Achieved on Beam Line 14-1

Light was successfully introduced into the experimental hutch of the newest SSRL beam line the morning of Wednesday, April 8. BL14-1 is a macromolecular crystallography branch line mostly funded by Genentech and the Joint Center for Structural Genomics (through funding from National Institutes of Health's National Institute of General Medical Sciences' Protein Structure Initiative).

Building beam lines is a complex endeavor involving many groups at SSRL and SLAC. Daniel Harrington, who served as project manager for construction of this beam line, sent a message to staff acknowledging the contributions of a long list of individuals in virtually every group at SSRL without whose commitment and hard work this project would not have gone so smoothly. see also:

8.   SSRL X-ray/VUV Proposals due June 1
       (contact: (contact: C. Knotts,

In response to user requests, we have increased the frequency of calls for proposals to conduct X-ray/VUV experiments at SSRL. New proposals can now be submitted June 1, September 1, or December 1. In addition, we eliminated the distinction between single experiment and program proposals, so that we have just one type of standard proposal valid for two years. For more information on proposal deadlines, instructions, and forms see:

9.   Photon Science Faculty Members Awarded Endowed Chairs
      (contact: B. Hedman,

Todd Martinez
Phil Bucksbaum

As announced by Stanford University, two members of the Photon Science Faculty have been awarded Endowed Chairs, effective April 14, 2009 Todd Martinez now holds the "David Mulvane Ehrsam and Edward Curtis Franklin Professorship in Chemistry" and Philip Bucksbaum the "Marguerite Blake Wilbur Professorship in Natural Science".

10.   New Era of Research Begins as World's First Hard X-ray Laser Achieves "First Light"
       April 21, 2009 SLAC National Accelerator Laboratory Press Release

LCLS 1st Light
The world's brightest x-ray source sprang to life last week at the U.S. Department of Energy's SLAC National Accelerator Laboratory. The Linac Coherent Light Source (LCLS) offers researchers the first-ever glimpse of high-energy or "hard" x-ray laser light produced in a laboratory.

When fine tuning is complete, the LCLS will provide the world's brightest, shortest pulses of laser x-rays for scientific study. It will give scientists an unprecedented tool for studying and understanding the arrangement of atoms in materials such as metals, semiconductors, ceramics, polymers, catalysts, plastics, and biological molecules, with wide-ranging impact on advanced energy research and other fields.

"This milestone establishes proof-of-concept for this incredible machine, the first of its kind," said SLAC Director Persis Drell. "The LCLS team overcame unprecedented technical challenges to make this happen, and their work will enable frontier research in a host of fields. For some disciplines, this tool will be as important to the future as the microscope has been to the past."

Even in these initial stages of operation, the LCLS x-ray beam is brighter than any other human-made source of short-pulse, hard x-rays. Initial tests produced laser light with a wavelength of 1.5 Angstroms, or 0.15 nanometers-the shortest-wavelength, highest-energy x-rays ever created by any laser. To generate that light, the team had to align the electron beam with extreme precision. The beam cannot deviate from a straight line by more than about 5 micrometers per 5 meters-an astounding feat of engineering. Read more in the full press release

11.   LCLS User Research Administration Update

H. Kamil
We are pleased to announce that we have filled the position of LCLS User Research Administrator Manager. Henia Kamil, formerly Manager of Academic Programs at the University of Michigan College of Engineering, joined us in March. Henia will be part of the User Research Administration team, with functional responsibilities to the LCLS Experimental Facilities Division. Earlier this month, Henia distributed the very first LCLS user newsletter, and she is already working on the next issue. With LCLS construction wrapping up, commissioning activities ramping up, milestones being reached, and preparations underway for the first user experiments at the LCLS later this summer, this is an extremely exciting time. So, stay tuned for more LCLS user news in the coming weeks and months. If you would like to join the mailing list to receive future LCLS user newsletters, contact Henia Kamil,

12.   LCLS Proposals for AMO and SXR Instruments due May 15, 2009
      (contact: H. Kamil,

The Linac Coherent Light Source is quickly approaching completion, with first laser light anticipated this summer. With construction on the Atomic, Molecular and Optical science instrument and Soft X-Ray beam line underway, the LCLS team has released a second call for scientific proposals. Researchers are invited to submit proposals for experiments to be conducted between March and July 2010 on these two experimental stations. Proposals must be submitted by May 15, 2009.

More information about the call for proposals and detailed descriptions of the instruments are available on the LCLS Web site. Specific questions about the AMO science instrument should be directed to John Bozek ( and about the SXR beam line to Michael Rowen (

For proposal submission see:

13.   Photon Science-Related Workshops, Conferences and Schools


SSRL Headlines is published electronically monthly to inform SSRL users, sponsors and other interested people about happenings at SSRL. SSRL is a national synchrotron user facility operated by Stanford University for the U.S. Department of Energy Office of Basic Energy Sciences. Additional support for the structural biology program is provided by the DOE Office of Biological and Environmental Research, the NIH National Center for Research Resources and the NIH Institute for General Medical Sciences. Additional information about SSRL and its operation and schedules is available from the SSRL WWW site.


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Last Updated: 30 APR 2009
Content Owner: L. Dunn
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