Cryo-EM undiscloses structural and mechanistic details on iron hijacking by $Staphylococcus aureus$: An insight into the interaction of IsdB hemophore with human hemoglobin.

Iron is an essential nutrient for almost all organisms and in the human body is primarily bound to the heme cofactor of hemoglobin (Hb), myoglobin and other heme-binding proteins. During infection, $Staphylococcus aureus$ exploits Hb heme pool as favored iron source, capturing and internalizing it by cell wall hemophores. The first step is performed by IsdB, which intercepts free Hb and extracts heme. IsdB, a proven virulence factor, is an attractive putative target for antimicrobials development but its mechanism of action needs to be further detailed. To this aim, we used cryo-EM single-particle analysis to study IsdB:Hb complex formation and heme extraction. The key complexes before and after heme extraction were solved at 2.9 and 5.8 $\mathring{a}$ngstroem resolution using carboxyHb, resistant to heme removal, and oxidized Hb, the physiologic IsdB substrate. IsdB first binds to Hb beta-chains, enhancing Hb dimerization to favor a second IsdB molecule binding to alpha-chains before extraction. These results greatly improve our current knowledge of IsdB structural and functional dynamics, thus promoting future studies on new potential antimicrobials aimed at impairing $S. aureus$ iron acquisition.