Cryo-EM structure of Helicobacter pylori urease with an inhibitor in the active site at 2.0Å resolution

Infection of the human stomach by Helicobacter pylori remains a worldwide problem and greatly contributes to peptic ulcer disease and gastric cancer. Without active intervention approximately 50% of the world population will continue to be infected with this gastric pathogen. Current eradication, called triple therapy, entails a proton-pump inhibitor and two broadband antibiotics, however resistance to either clarithromycin or metronidazole is greater than 25% and rising. Therefore, there is an urgent need for a targeted, high-specificity eradication drug. Gastric infection by H. pylori depends on the expression of a nickel-dependent urease in the cytoplasm of the bacteria. Here, we report the 2.0 angstrom resolution structure of the 1.1 MDa urease in complex with an inhibitor by cryo-electron microscopy and compare it to a beta -mercaptoethanol-inhibited structure at 2.5 angstrom resolution. The structural information is of sufficient detail to aid in the development of inhibitors with high specificity and affinity. Infection by Helicobacter pylori is associated with peptic ulcers and gastric cancer. H. pylori urease is required for colonization of the stomach and thus an attractive antimicrobial drug target. Cryo-EM analyses of the H. pylori urease with inhibitors bound reveal structural details useful in rational drug design.

Automated summary

H. pylori infection is linked to peptic ulcers and gastric cancer, and the urease enzyme is crucial for stomach colonization, making it an attractive antimicrobial drug target. Cryo-EM analysis of H. pylori urease with inhibitors bound provides structural insights valuable for rational drug design.