PROBING THE HEME-BINDING POCKET OF MYCOBACTERIUM TUBERCULOSIS HEME-DEGRADER RV35

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Iron is a necessary nutrient for living organisms, including Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. However, during infection of its human host, hemoglobin-bound heme is the predominant source of iron. Heme acquisition in Mtb is facilitated by a novel pathway where heme is (1) sequestered from hemoglobin by a secreted hemophore, (2) transferred across the membrane by heme transporters and (3) metabolized by a cytosolic heme-degrader. From our most recent data collection at SSRL (Dec ?08), we determined a 1.8 ¿ resolution structure of the Mtb heme-degrader, Rv3592, in complex with heme. Each monomer of dimeric Rv3592 binds to two molecules of heme, a surprising revelation as initial biochemical data is consistent with a 1:1 stoichiometry. Furthermore, the heme molecules are stacked on each other with a histidine residue (His75) as the proximal ligand for the solvent exposed heme. Currently, we have assigned the distal ion ligand of the solvent-protected heme as a chloride atom.