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

Nat Commun. 2021 Jan 11;12(1):230. doi: 10.1038/s41467-020-20485-6.

Abstract

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 Å resolution structure of the 1.1 MDa urease in complex with an inhibitor by cryo-electron microscopy and compare it to a β-mercaptoethanol-inhibited structure at 2.5 Å resolution. The structural information is of sufficient detail to aid in the development of inhibitors with high specificity and affinity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Cryoelectron Microscopy*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Helicobacter pylori / enzymology*
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Urease / antagonists & inhibitors*
  • Urease / ultrastructure*

Substances

  • Enzyme Inhibitors
  • Urease