Structural insights into zinc piracy by Neisseria gonorrhoeae to overcome nutritional immunity.

With an estimated 106 million global cases annually, Neisseria gonorrhoeae (Ngo) poses a significant public health problem. Ngo demonstrates a remarkable capacity to overcome nutritional immunity through the deployment of specialized transporters that pirate metals such as zinc from human proteins such as calprotectin (hCP). We report the cryo-EM structure of Ngo TdfH in complex with a heterotetramer of hCP. An extensive binding interface is mediated almost entirely by the S100A9 subunits of hCP. Mutagenesis studies of residues in the large binding interface reveal minimal effects from single-site mutations, whereas larger truncations disrupt binding and function. These results support a mechanistic model based on the large interaction interface overcoming a steric clash between α-helix III of S100A9 and loops 5 and 9 of TdfH, which leads to the distortion of the proximal His6 site, followed by zinc release, and import through the barrel domain.