title: Mycobacterium tuberculosis hemoglobin N displays a protein tunnel suited for O2 diffusion to the heme.
abstract: 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.
authors.affiliation: Department of Physics-INFM and Advanced Biotechnology Center-IST, University of Genova, Largo Rosanna Benzi 10. 16132 Genova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Milani
authors.forename: A
authors.initials: A
authors.lastname: Pesce
authors.forename: Y
authors.initials: Y
authors.lastname: Ouellet
authors.forename: P
authors.initials: P
authors.lastname: Ascenzi
authors.forename: M
authors.initials: M
authors.lastname: Guertin
authors.forename: M
authors.initials: M
authors.lastname: Bolognesi
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006418:Heme / Q000378:metabolism*; D006454:Hemoglobins / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis; D010100:Oxygen / Q000378:metabolism*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D054793:Truncated Hemoglobins
chemical_list: D006454:Hemoglobins; D008024:Ligands; D054793:Truncated Hemoglobins; D006418:Heme; D010100:Oxygen