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

• Published in: Nature communications Vol. 12; no. 1; pp. 230 - 8
• Main Authors: Cunha, Eva S., Chen, Xiaorui, Sanz-Gaitero, Marta, Mills, Deryck J., Luecke, Hartmut
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 147/28; 631/154; 631/326/421; 631/45/607/1164; 631/535/1258/1259; Antibiotics; Antiinfectives and antibacterials; Antimicrobial agents; Broadband; Cancer; Catalytic Domain; Clarithromycin; Colonization; Cryoelectron Microscopy; Cytoplasm; Drug development; Electron microscopy; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Eradication; Gastric cancer; Helicobacter pylori; Helicobacter pylori - enzymology; Humanities and Social Sciences; Hydrogen-Ion Concentration; Infections; Inhibitors; Metronidazole; Models, Molecular; multidisciplinary; Nickel; Peptic ulcers; Proton pump inhibitors; Science; Science (multidisciplinary); Stomach; Therapeutic targets; Ulcers; Urease; Urease - antagonists & inhibitors; Urease - ultrastructure; World population
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20485-6

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. 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.