Hartmut Leucke / UC Irvine A three-dimensional view of a key molecular structure in the Helicobacter pylori bacterium, built with data derived from protein crystallography experiments at the Stanford Synchrotron Radiation Lightsource. Download image

Ulcer bug’s Achilles’ heel revealed in UCI-led study

X-ray experiments pinpoint drug target in bacteria that affect millions worldwide

Irvine, Calif., Dec. 11, 2012 Research led by a UC Irvine structural biologist has revealed a potential new way to attack common stomach bacteria that cause ulcers and significantly increase the odds of developing stomach cancer.

Hartmut “Hudel” Luecke, professor of molecular biology & biochemistry, and colleagues focused on the bacterium Helicobacter pylori, which is capable of living in strong stomach acid. At least half the world’s population carries H. pylori, and hundreds of millions suffer health problems as a result. Current treatments require a complicated regimen of stomach acid inhibitors and antibiotics.

The researchers ultimately determined the three-dimensional molecular structure of a key bacterial protein, revealing a very promising drug target. “We were looking for a means to disrupt H. pylori’s own mechanism for protecting itself against stomach acid,” Luecke said. Study results were published online Dec. 10 in Nature.

He and his team conducted experiments at the U.S. Department of Energy’s SLAC National Accelerator Laboratory, using powerful X-rays from SLAC’s Stanford Synchrotron Radiation Lightsource.

They zeroed in on tiny channels that H. pylori uses to allow the entry of urea from gastric juices in the stomach; it then breaks down this compound into ammonia, which neutralizes stomach acid. Blocking the channels would disable this protective system, creating a potential new treatment.

The channels are formed by a protein embedded in the bacterium’s cell membrane, and membrane proteins are notoriously difficult to crystallize – a prerequisite for protein crystallography, the main technique for determining protein structures. This technique bounces X-rays off electrons in the crystallized protein to generate data used to build a 3-D map of how the protein’s atoms are arranged.

Luecke, who directs the UCI Center for Biomembrane Systems, noted that in addition to the basic challenge of crystallizing membrane proteins, for this experiment, “we needed to grow and screen thousands of crystals.”

“We collected more than 100 separate data sets and tried numerous structural determination techniques,” said Mike Soltis of Stanford Synchrotron Radiation Lightsource, who worked with Luecke and his team to produce a 3-D map of the atomic structure.

“This is the hardest structure I’ve ever deciphered, and I’ve been doing this since 1984,” Luecke said. “You have to try all kinds of tricks, and these crystals fought us every step of the way. But now that we have the structure, we’ve reached the exciting part: the prospect of creating specific, safe and effective ways to target this pathogen and wipe it out.”

Reginald McNulty and Chiung-Kuang Chen of UCI and David Strugatsky, Keith Munson and George Sachs of UCLA also participated in the study, which was supported by the National Institutes of Health, the National Cancer Institute, the UCI Center for Biomembrane Systems and the U.S. Department of Veterans Affairs.

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