U.S. Department of Health and Human Services

Molecule Critical for Gut Pathogen Survival Visualized

​Researchers have revealed the structure of a protein complex important for the survival of a species of bacteria that causes gastric ulcers and other gastrointestinal diseases. Helicobacter pylori (H. pylori) is a species of bacteria that is commonly found living in the human stomach. It is thought to damage the mucus coating that protects the stomach lining, exposing it to powerful digestive acids. This can result in gastric ulcers, which are painful sores that can be accompanied by such symptoms as weight loss, vomiting, and bleeding. Antibiotics are typically used to treat H. pylori infections, but they are not always successful and can cause the bacterium to develop antibiotic resistance. This bacterium may have an Achilles’ heel, however, as it can only survive the harsh environment of the stomach by neutralizing the potent stomach acids that would otherwise digest the bacterium. It does this by taking up a molecule called urea through a selective opening, a “channel,” on the surface of the bacterium. Once inside, the urea is converted into ammonia, which is then used to neutralize the stomach acid. This channel is an ideal target for drugs that can block the entry of urea into the bacterium, thereby threatening its survival, and determining the three-dimensional structure of the channel is necessary before drugs can be designed efficiently.

To obtain the structure, a group of scientists undertook the extremely dificult task of collecting large amounts of the protein complex that creates the channel, purifying it, and condensing it into crystals. They were then able to deduce the structure of the complex by analyzing the pattern made by X-rays after they passed through the crystals, a technique called X-ray diffraction, the same approach that was used to discover the double helix structure of DNA. The result of the study was the generation of an elegant, three-dimensional model of the channel that H. pylori uses to stay alive inside the stomach. The scientists were then able to identify the precise segment that is required for urea entry by changing parts of the channel and testing its ability to take up urea. Now that the detailed structure and critical features of the channel have been deined, scientists can design speciic drugs that will block its function, like designing a plug to it into a hole, thereby preventing the entry of urea into H. pylori and, ultimately, impeding its survival in the stomach. This would provide a new strategy to combat this pathogen and open the possibility of new treatments for the prevention of ulcers.

Strugatsky D, McNulty R, Munson K, et al. Structure of
the proton-gated urea channel from the gastric pathogen
Helicobacter pylori. Nature 493: 255-258, 2013.