Driving Biomedical Projects Portfolio of the Resource for Native MS Guided Structural Biology

蛋白质通常通过作为多个蛋白质的组装体工作来执行其功能， 生物分子或配体结合。蛋白质复合物/组装体的表征，包括所有 结合配偶体，它们在复合物中的相对结构/拓扑结构，结合时的构象变化， 伴侣的相对结合亲和力是更好地理解这些复合物如何 系统执行其正常的生物功能，以及结构的改变如何导致故障。 MS正在成为结构生物学的强大工具，多种MS方法的组合使 生物大分子的结构表征。然而，MS仪器和 在常规、可靠和快速的结构表征中， 问题研究推进用于结构生物学应用的天然MS的技术开发， 为了说明原生MS如何指导和整合其他结构生物学方法，我们确定了 存在重大技术挑战的三种主要蛋白质复合物，迫使PI 使用多种结构生物学方法。这些是1）蛋白质：蛋白质，2）膜蛋白和膜 蛋白质：脂质复合物，和3）RNA：蛋白质，复合物。选择DBPs是为了涵盖以下项目： 高度生物医学意义，其进展取决于解决重大技术挑战。这些 项目将从改进的原生MS工作流程中受益匪浅。解决他们的结构性挑战， 他们使用的其他结构工具的上下文，也将提供适用于 更广泛的研究人员。有效的沟通是DBPs取得进展的关键， 资源充分理解正在解决的生物问题的性质， 调查人员充分了解每种技术的现有能力。最初的项目会议 为每一个消毒副产品举行了会议，并获得了初步数据。定期举行会议， 评估进展并计划未来的实验。鼓励DBP研究人员及其小组 在他们参加的会议上介绍工作，并适当承认 nMS SMB资源。 DBP将被视为成功完成时，它已达到一个点，其中多个高质量的 手稿准备和出版，DBP的问题可以用现有的技术来回答， 阶段，并且DBP不再驱动资源以改进原生MS技术。该资源将 参与撰写和准备每一份相关的联合手稿。用于出版、期刊 将有针对性的，具有高影响力，并由广大社区阅读，这有助于我们的传播 计划将这项技术带给广泛的受众，包括结构生物学家和生物医学研究人员。

Proteins often carry out their functions by working as assemblies of multiple proteins, with or without other biomolecules or ligands bound. Characterization of protein complexes/assemblies, including identification of all binding partners, their relative architecture/topology in the complex, conformational changes upon binding and the relative binding affinities of partners is key to developing a better understanding of how these complex systems carry out their normal biological functions and how alterations of architecture can lead to malfunction. MS is emerging as a powerful tool for structural biology, with the combination of multiple MS approaches enabling the structural characterization of biomacromolecules. However, development of both MS instrumentation and methods is necessary to fully implement the use of MS in routine, reliable, and rapid structural characterization studies. To advance the technological development of native MS for structural biology applications and to illustrate how native MS can guide and integrate with other structural biology approaches, we have identified three main classes of protein complexes for which significant technological challenges exist, compelling PIs to use multiple structural biology approaches. These are 1) protein:protein, 2) membrane protein and membrane protein:lipid complexes, and 3) RNA:protein, complexes. The DBPs were selected to encompass projects with high biomedical significance where progress depends on solving substantial technical challenges. These projects will benefit significantly from improved native MS workflows. Solving their structural challenges, in the context of other structural tools that they use, will also provide solutions and guidance that are applicable to a much broader spectrum of researchers. Effective communication is key to the progress of the DBPs, so that the Resource fully understands the nature of the biological problem being addressed and so that the collaborating investigators fully understand the current capabilities of each of the technologies. Initial project meetings have been held for each of the DBPs and preliminary data have been obtained. Regular meetings will be held to assess the progress and plan future experiments. DBP investigators and their groups will be encouraged to present the work at conferences they attend, with an appropriate acknowledgement of the nMSSB Resource. A DBP will be considered successfully completed when it has reached a point where multiple high-quality manuscripts are prepared and published, the DBP’s questions can be answered with technology existing at that stage, and the DBP is no longer driving the Resource to improve the native MS technology. The Resource will be involved with the authoring and preparation of each of the relevant joint manuscripts. For publication, journals will be targeted that have high-impact and are read by the broad community, which aids in our dissemination plan of bringing the technology to a broad audience, including structural biologists and biomedical researchers.