Mechanism of transport by the Anthrax virulence-determinant MntBC-A

Bacillus anthracis, the causative agent of Anthrax, is a lethal human pathogen. Recently, B. anthracis has become notorious due to its use as a biological weapon. The lethalness of B. anthracis depends on its ability to scavenge transition metals in the host environment since these metals are essential for its survival in the host. MntBC-A is a metal import system of unknown function which has been shown to be absolutely essential for the virulence and lethalness of B. anthracis. Here, we combined computational and experimental approaches to study the function of MntBC-A. We find that MntBC-A is a very specific metal importer, transporting only manganese into the cytosol of this pathogen. This finding highlights the importance of this metal for progression of Anthrax. We also find that zinc can be used as a high-affinity inhibitor, paving the way for future intervention strategies. Computational analysis shows that the transmembrane metal permeation pathway is lined with six titratable residues, which we demonstrate to be essential for manganese import. Modelling suggests that access to these titratable residues is blocked by a ladder of hydrophobic residues, and ATP-driven conformational changes open and close this hydrophobic seal to permit metal binding and release. The conservation of this arrangement of titratable and hydrophobic residues among other transporters of transition metals suggests a common mechanism. The findings advance our understanding of transmembrane metal recognition and permeation and may aid the design and development of inhibitors.