High Resolution Structural Characterisation and Structure-Based Drug Discovery Targeting a Crucial Metalloenzyme of Methicillin Resistant Staphylococc

我们以前的文献已经证明了一种独特的超氧化物歧化酶(SOD)金属酶在革兰氏阳性致病菌金黄色葡萄球菌感染过程中的关键作用。这种金黄色葡萄球菌特有的超氧化物歧化酶在宿主体内宿主定植期间经历的锰饥饿期间能够维持强大的超氧化物歧化酶防御方面发挥了关键作用。我们测定了它的X射线晶体结构，并进行了详细的生化研究，以研究其金属专一性。在这里，我们将(I)通过中子衍射(ND)确定超氧化物歧化酶的结构以定位质子/水，(Ii)确定这种不同寻常的超氧化物歧化酶的催化机理，以及(Iii)测试现有的，并筛选作为潜在治疗线索和研究工具的新型化学抑制剂。ND的应用将使基础发现成为可能(确定作用机制和金属特异性)，同时提供支持药物发现计划的新颖结构数据。

Our prior publications have demonstrated a crucial role for a unique superoxide dismutase (SOD) metalloenzyme in the Gram positive pathogenic bacterium Staphylococcus aureus during infection. This S. aureus-specific SOD plays a key role in enabling a robust superoxide defence to be maintained during the host-imposed manganese starvation the bacterium experiences in vivo during host colonisation. We have determined X-ray crystal structures and performed detailed biochemistry to study its metal specificity. Here, we will (i) determine the SOD structure by neutron diffraction (ND) to localise protons/waters, (ii) determine the catalytic mechanism of this unusual SOD, and (iii) test existing, and screen for novel chemical inhibitors as potential therapeutic leads and as research tools. Application of ND will enable fundamental discoveries (determining mechanism of action and of metal specificity) while providing novel structural data that will underpin drug discovery programs.