Selective binding of antimicrobial porphyrins to the hame-receptor IsdH-NEAT3 of Staphylococcus aureus.
Selective binding of antimicrobial porphyrins to the hame-receptor IsdH-NEAT3 of Staphylococcus aureus.
复制标题
抗菌卟啉与金黄色葡萄球菌的 hame 受体 IsdH-NEAT3 的选择性结合。
DOI：
10.1002/pro.2276
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发表时间：
2013
期刊：
影响因子：
8
通讯作者：
Nhuan Vu
中科院分区：
文献类型：
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作者：
(編者)本村凌二;(著者)本村凌二;井上秀太郎;中西麻澄;池口守;樋脇博敏;渡辺耕;中川亜希;島田誠;長谷川敬;志内一興;伊藤雅之;橋本資久;宮崎亮;澤田典子;岡田泰介;佐藤昇;田中創;上野愼也;三津間康幸;高橋亮介;大清水裕;Yoshitaka Moriwaki;Nhuan Vu
人类病原体金黄色葡萄球菌的Isd（铁调节表面决定因子）系统，负责从宿主生物获得血红素。我们最近报道了细胞外血红素受体IsdH‐NEAT3捕获并转移含氧化态金属的非铁抗菌卟啉（III）。然而，几何因素如金属的大小（离子半径）是否影响金属卟啉的结合和转移尚不清楚。我们对抗菌铟(III) -卟啉的结合特性进行了充分的结构、功能和热力学分析，它比天然配体血红素的铁（III）携带更大的金属离子。结果表明，NEAT3受体以与血红素非常相似的方式识别含In（III）的PPIX。位点定向突变从晶体结构中发现Tyr642是识别机制的中心元素。重要的是，NEAT3受体具有捕获金属卟啉二聚体的非凡能力。分子动力学模拟表明，IsdH‐NEAT3不需要改变构象，也不需要在其结合位点内对残基进行大的重排，以适应更大的（血红素）2配体。我们讨论了这些发现对设计针对s关键受体家族的有效抑制剂的意义。葡萄球菌。
The Isd (iron‐regulated surface determinant) system of the human pathogenStaphylococcus aureusis responsible for the acquisition of heme from the host organism. We recently reported that the extracellular heme receptor IsdH‐NEAT3 captures and transfers noniron antimicrobial porphyrins containing metals in oxidation state (III). However, it is unclear if geometric factors such as the size of the metal (ionic radius) affect binding and transfer of metalloporphyrins. We carried out an ample structural, functional, and thermodynamic analysis of the binding properties of antimicrobial indium(III)‐porphyrin, which bears a much larger metal ion than the iron(III) of the natural ligand heme. The results demonstrate that the NEAT3 receptor recognizes the In(III)‐containing PPIX in a manner very similar to that of heme. Site‐directed mutagenesis identifies Tyr642 as the central element in the recognition mechanism as suggested from the crystal structures. Importantly, the NEAT3 receptor possesses the remarkable ability to capture dimers of metalloporphyrin. Molecular dynamics simulations reveal that IsdH‐NEAT3 does not require conformational changes, or large rearrangements of the residues within its binding site, to accommodate the much larger (heme)2ligand. We discuss the implications of these findings for the design of potent inhibitors against this family of key receptors ofS. aureus.