Macrophage-generated
oxygen- and
nitrogen-reactive species control the development of
Mycobacterium tuberculosis infection in the host. Mycobacterium tuberculosis '
truncated hemoglobin' N (trHbN) has been related to
nitric oxide (NO) detoxification, in response to macrophage nitrosative stress, during the bacterium
latent infection stage. The three-dimensional structure of oxygenated trHbN, solved at 1.9 A resolution, displays the two-over-two alpha-helical sandwich fold recently characterized in two homologous
truncated hemoglobins, featuring an extra N-terminal alpha-helix and homodimeric assembly. In the absence of a polar distal E7 residue, the O2
heme ligand is stabilized by two hydrogen bonds to TyrB10(33). Strikingly,
ligand diffusion to the
heme in trHbN may occur via an apolar tunnel/cavity system extending for approximately 28 A through the
protein matrix, connecting the
heme distal cavity to two distinct
protein surface sites. This unique structural feature appears to be conserved in several homologous
truncated hemoglobins. It is proposed that in trHbN,
heme Fe/O2 stereochemistry and the
protein matrix tunnel may promote O2/NO chemistry in vivo, as a M.
tuberculosis defense mechanism against macrophage nitrosative stress.