Nickel import and export in the human pathogen Helicobacter pylori, perspectives from molecular modelling

The uptake of essential metal ions and the ability to extrude them when their excess causes toxicity are crucial processes for all living beings. Nickel is a virulence factor for several human pathogens and in particular for the human gastric pathogen Helicobacter pylori because of its crucial role in the catalytic activity of two Ni-dependent enzymes, urease and hydrogenase. H. pylori requires efficient uptake mechanisms to import Ni(II) because of its scarcity in the human body, but themolecular details of Ni(II) homeostasis are not fully known. Here we offer a structural framework for the machinery of Ni(II) import/export in H. pylori, obtained through comparative modelling and macromolecular docking. The model structures reported in this perspective are initial steps towards the understanding of these processes at the molecular level and in the direction to exploit them to eradicate infections caused by this family of pathogens. The differences between the structural models obtained by using both the recently released neural networkbased approach implemented in AlphaFold2 and a more classical user-driven modelling procedure are also discussed.

Automated summary

The uptake and extrusion of essential metal ions are crucial processes for all living beings, with Helicobacter pylori's dependence on nickel being particularly important. The molecular details of Ni(II) homeostasis in the human body are not yet fully known. This study provides a structural framework for understanding the machinery of Ni(II) import/export in H. pylori and discusses differences between structural models obtained using neural network-based approaches and traditional user-driven modeling procedures.