Duran Gizem Nur, Özbil Mehmet
Department of Chemistry, Marmara University, İstanbul Turkey.
Institute of Biotechnology, Gebze Technical University, Kocaeli Turkey.
Turk J Chem. 2021 Aug 27;45(4):1146-1154. doi: 10.3906/kim-2102-25. eCollection 2021.
Gram-negative bacterium Neisseria meningitidis, responsible for human infectious disease meningitis, acquires the iron (Fe) ion needed for its survival from human transferrin protein (hTf). For this transport, transferrin binding proteins TbpA and TbpB are facilitated by the bacterium. The transfer cannot occur without TbpA, while the absence of TbpB only slows down the transfer. Thus, understanding the TbpA-hTf binding at the atomic level is crucial for the fight against bacterial meningitis infections. In this study, atomistic level of mechanism for TbpA-hTf binding is elucidated through 100 ns long all-atom classical MD simulations on free (uncomplexed) TbpA. TbpA protein underwent conformational change from 'open' state to 'closed' state, where two loop domains, loops 5 and 8, were very close to each other. This state clearly cannot accommodate hTf in the cleft between these two loops. Moreover, the helix finger domain, which might play a critical role in Fe ion uptake, also shifted downwards leading to unfavorable Tbp-hTf binding. Results of this study indicated that TbpA must switch between 'closed' state to 'open' state, where loops 5 and 8 are far from each other creating a cleft for hTf binding. The atomistic level of understanding to conformational switch is crucial for TbpA-hTf complex inhibition strategies. Drug candidates can be designed to prevent this conformational switch, keeping TbpA locked in 'closed' state.
革兰氏阴性细菌脑膜炎奈瑟菌可引发人类感染性疾病脑膜炎，它从人类转铁蛋白（hTf）中获取生存所需的铁（Fe）离子。对于这种转运过程，细菌会促进转铁蛋白结合蛋白TbpA和TbpB发挥作用。没有TbpA，转运就无法发生，而缺少TbpB只会减缓转运速度。因此，在原子水平上理解TbpA与hTf的结合对于对抗细菌性脑膜炎感染至关重要。在本研究中，通过对游离（未复合）的TbpA进行100纳秒的全原子经典分子动力学模拟，阐明了TbpA与hTf结合的原子水平机制。TbpA蛋白经历了从“开放”状态到“闭合”状态的构象变化，其中两个环结构域，即环5和环8，彼此非常靠近。这种状态显然无法在这两个环之间的裂隙中容纳hTf。此外，可能在铁离子摄取中起关键作用的螺旋指结构域也向下移动，导致Tbp与hTf的结合不利。本研究结果表明，TbpA必须在“闭合”状态和“开放”状态之间切换，在“开放”状态下，环5和环8彼此远离，形成一个用于hTf结合的裂隙。对构象转换的原子水平理解对于TbpA - hTf复合物抑制策略至关重要。可以设计候选药物来阻止这种构象转换，使TbpA锁定在“闭合”状态。
