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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 铁是生物体的必需营养素，包括结核分枝杆菌（Mtb），结核病的病原体。然而，在感染人类宿主期间，血红蛋白结合的血红素是铁的主要来源。血红素在结核分枝杆菌中的获取是通过一种新的途径促进的，其中血红素（1）通过分泌的血细胞从血红蛋白中分离出来，（2）通过血红素转运蛋白跨膜转移，（3）通过胞质血红素降解剂代谢。从我们最近在SSRL（12月？08），我们确定了与血红素复合的Mtb血红素降解剂Rv 3592的1.8？分辨率结构。二聚体Rv 3592的每个单体与两个血红素分子结合，这是一个令人惊讶的发现，因为初始生化数据与1：1化学计量一致。此外，血红素分子彼此堆叠，其中组氨酸残基（His 75）作为溶剂暴露的血红素的近侧配体。目前，我们已经分配的远端离子配体的溶剂保护的血红素作为氯原子。

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.