Acquisition of a 700 MHz NMR CryoProbe

获取 700 MHz NMR CryoProbe

• 批准号: 10387885
• 负责人: JEAN S BAUM
• 金额: $ 22.12万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387885
• 关键词: 2019-nCoV; ACE2; Address; Affect; Amyloid Fibrils; Amyloid deposition; Biological; Biophysics; Cell physiology; Cells; Cellular Assay; Collagen Fibril; Complex; Computing Methodologies; Disease; Event; Fibrillar Collagen; Goals; Health; Homeostasis; Intervention; Lewy Bodies; Measures; Mediating; Molecular; Molecular Conformation; Motion; Parkinson Disease; Pathologic; Platelet aggregation; Property; Protein Dynamics; Proteins; SARS-CoV-2 spike protein; System; Therapeutic; alpha synuclein; biophysical properties; biophysical tools; design; dynamic system; instrumentation; monomer; nanoscale; protein protein interaction; receptor binding; self assembly; solid state nuclear magnetic resonance; synucleinopathy

Abstract The overarching goal in this proposal is to understand how molecular motions and biophysical properties modulate protein interactions to promote normal homeostasis or pathological disease states. We investigate the relationship between protein dynamics and interactions in three contexts: 1) protein–fibrillar collagen interactions involved in platelet aggregation; 2) α-synuclein (αS), an intrinsically disordered protein (IDP) whose misfolding and aggregation into amyloid fibrils and deposition into Lewy bodies are associated with debilitating synucleinopathies, such as Parkinson's Disease; and 3) the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), whose interaction with angiotensin converting enzyme 2 (ACE2) via the receptor binding domain (RBD) is the initial point of host cell entry. We have recently discovered that in each of these cases, conformational dynamics profoundly impact their atomic-to-nano scale properties and may affect their potential for biomolecular interactions. Despite the biological importance of these systems and the implications for their interactions on disease, the molecular determinants of these protein–protein interactions remain unanswered. Thus, we use a multifaceted approach integrating solution and solid-state NMR with biophysical, biological, and computational methods to address how molecular motions modulate protein interactions to promote normal homeostasis or pathological disease states. Gaining a molecular understanding of protein–protein interactions with each of these dynamic systems relies on state- of-the-art solution NMR instrumentation to be able to accurately measure timescales and fluctuations of these interaction events and to detect transient, lowly populated complexes.

摘要 这项计划的首要目标是了解分子运动和生物物理特性 调节蛋白质相互作用以促进正常稳态或病理疾病状态。我们调查 蛋白质动力学和相互作用之间的关系在三个方面：1）蛋白质-纤维胶原 2）α-突触核蛋白（αS），一种内在无序蛋白（IDP） 其错误折叠和聚集成淀粉样纤维并沉积成路易体与 使人衰弱的突触核蛋白病，如帕金森氏病;和3）严重急性帕金森氏病的刺突糖蛋白。 呼吸综合征冠状病毒2型（SARS-CoV-2），与血管紧张素转换酶2相互作用 通过受体结合结构域（RBD）与ACE 2结合是宿主细胞进入的起始点。我们最近 发现在每一种情况下，构象动力学都深刻地影响着它们的原子到纳米尺度 性质，并可能影响其生物分子相互作用的潜力。尽管生物学上的重要性， 这些系统及其相互作用对疾病的影响，这些系统的分子决定因素， 蛋白质-蛋白质相互作用仍然没有答案。因此，我们使用多方面的方法整合解决方案 和固态核磁共振与生物物理，生物和计算方法，以解决如何分子 运动调节蛋白质相互作用以促进正常的体内平衡或病理疾病状态。获得 对蛋白质-蛋白质相互作用的分子理解与这些动态系统中的每一个都依赖于状态- 最先进的溶液NMR仪器能够准确地测量这些的时间尺度和波动， 相互作用事件，并检测瞬态，低填充复合物。