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Researchers employ state-of-the-art synchrotron radiation tools for studying protein structures

By Elizabeth Gardner

Sept. 9, 2002 | Synchrotron radiation laboratories are large sources of X-rays used to study materials at the

Crystal method: A close-up view of the MAR detector. The sample sits on the detector system, at the near end of the pin. The device, an Oxford Cryostream, on the near side pointing down at the sample delivers a stream of cold nitrogen gas, keeping the crystal cool. The horizontal shaft on the far side of the crystal rotates the crystal during data collection. 
molecular and atomic level. Synchrotron radiation is produced by accelerating electrons in a ring almost to the speed of light, causing them to emit photons. Beams of photons emerge from the accelerator ring through pipes called beamlines, set at intervals around the ring. Instruments at the ends of the beamlines hold samples of the material to be studied, and record what happens when they encounter the photon beam.

These beams can be used to study the 3-D structure of protein crystals through a process called X-ray diffraction, which measures how the X-rays scatter when they encounter the crystal. The resulting data produce a picture of the complex structure of the protein, including the shapes of all of the crannies to which drug molecules might be able to bind in order to change how the protein works.

Of the three dozen or so synchrotron labs around the world, Argonne National Laboratory's Advanced Photon Source (APS) in Illinois is one of the top three for structural biology applications. (The other two are in France and Japan.) Most synchrotron labs were designed to be optimized for "soft" X-rays, with energies below 4 kilo-electron volts (KeV). Built in the early 1990s, the APS is the newest synchrotron lab in the United States and is optimized for "hard" X-rays, or those with typical energies of about 20 KeV. High-throughput protein crystallography requires energies of about 5 to 10 KeV. (Special instrumentation allows users to "tune" the beam to the correct energy level for a particular study.) The APS is the most brilliant source of synchrotron radiation in the United States that is optimized for the energy ranges required by protein crystallography. A beamline at the APS can complete a protein study in 30 to 45 minutes, compared with several days using older methods.

Virtually all synchrotron labs now host protein crystallography research to some degree, and many have regular industrial users. But because of the brilliance and the high energy range of its X-rays, the APS is likely to be the leading U.S. facility for protein study for the next decade, says Director J. Murray Gibson. Of the APS' 70 beamlines, 18 are slated for structural biology. The APS hopes to build a structural genomics laboratory to support the work done on the beamlines.

"The demand will certainly be there — these are early times," says Gibson. "In 10 years, other tools like computer modeling might compete with synchrotrons, but for now, especially for the most difficult problems, the APS will be particularly attractive."

Structural GenomiX, the only company with sole ownership of a beamline at the APS, was in the right place at the right time when the facility was still relatively new and had just begun the process of allocating its beamlines and designating the scientific programs that would be served by each one. As a result, it has a huge share of a precious resource.

"This was an exciting and appropriate thing, given that we had the space," Gibson says. "But we're not likely to approve another [single-company proposal]. The APS is reaching another phase in its development where our sectors are filling up, and we have to make careful decisions. [Beamline operators] will have to perform and succeed."

Any company can obtain the temporary use of a beamline at a synchrotron lab, though it must compete with other users for a limited amount of beamtime. If it's doing nonproprietary research, it may have to convince the laboratory's management of the value of its research plans, relative to those of other would-be users. For proprietary research, it may simply have to pay a fee, generally ranging between $50 and $200 per hour, depending on which synchrotron facility is used.

Other companies active in structural biology with ownership or administrative authority over a beamline include:

  • Syrrx Inc.: Syrrx operates a beamline at the Advanced Light Source at Lawrence Berkeley Laboratory in Berkeley, Calif. Originally designed as a soft X-ray source, the Advanced Light Source was recently retrofitted so that it can produce hard X-rays on some beamlines, though not of the same brilliance as those at the APS.

  • The Industrial Macromolecular Crystallography Association: The IMCA, based in Chicago, operates two beamlines at the APS. Its membership roster features most of the big names in Big Pharma, including Abbott Laboratories, Bristol-Myers Squibb, GlaxoSmith-Kline, Procter & Gamble, Eli Lilly, Pfizer, Merck, Monsanto, Pharmacia, Schering-Plough, and 3-Dimensional Pharmaceuticals.

  • MediChem Life Sciences: MediChem's subsidiary, Advanced X-ray Analytical Services Inc. (AXAS), manages a beamline at the APS through the lab's Commercial Collaborative Access Team (COM-CAT) and administers fee-for-service access to other companies. MediChem is based in Lemont, Ill., and the $8.7-million beamline was funded by the state of Illinois.

—Elizabeth Gardner 

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