This preprint has been taken down.

Abstract

Gram-positive pathogenic bacteria acquire heme derived from the host hemoglobin as an iron source for their proliferation in blood. Since excess free heme is cytotoxic, they employ an ABC-type heme exporter, HrtBA, to overcome the toxicity. We biochemically characterized HrtBA, and determined the crystal structures of the exporter, alone and complexed with a heme analog or nucleotides. HrtBA adopts an eight transmembrane-helix structure with no substrate-translocation cavity, and thus is distinct from the classical ABC transporters with an alternating access mechanism. Our structural models revealed the sequential motions whereby HrtBA captures heme in the outer leaflet of the membrane, sequesters it in the transmembrane-helix bundle, and extrudes the bound heme upon ATP binding. The structural and functional data illustrate the novel efflux mechanism by which HrtBA detoxifies the heme accumulated in the membrane, providing insights toward antimicrobial agent development.