Macromolecular Diffraction Resource: MacCHESS

描述（由申请人提供）：康奈尔高能同步加速器光源（MacCHESS）的大分子衍射为开发新技术和推进结构生物学家以及更广泛的生物研究社区的研究目标提供了一个设施。MacCHESS还致力于培养未来的领导者，他们将能够将同步加速器科学和结构生物学的进步转化为有价值的生物医学应用。MacCHESS科学家的新技术研究和开发项目（TR& D）将在未来的资助期内继续由生物学和生物医学中的基本重要问题（即，推动生物医学项目或DBP）。DBPs包括旨在了解复杂的膜受体信号传导系统的研究，定义神经元功能中离子通道的调节，探索在关键代谢事件中发挥核心作用的酶的催化机制，以及描绘负责基因表达的复杂大分子组装。当这些过程被解除管制时，可能导致癌症和许多其他疾病的发展。提出的TR& D旨在帮助研究人员解决这些重要问题：1）生物小角X射线散射（BioSAXS）。BioSAXS应用的新技术正在开发中，以满足结构生物学社区日益增长的需求，以获得有关大分子复合物（例如生长因子受体，RNA剪接复合物）内的全局构象变化和/或其低聚状态在溶液中发生的变化的信息，并具有重要的功能后果。2)压力冷冻。这种独特的MacCHESS技术为捕获以前没有解决的重要蛋白质构象和酶中间状态提供了令人兴奋的可能性，并促进了“困难”晶体的结构测定。3)多个小晶体。许多直接参与激素和生长因子信号传导事件的膜相关复合物，以及重要的神经递质受体和离子通道，产生非常小或活性差的晶体。该项目将提高从这种晶体中获得有价值的结构信息的能力。4)大分子动力学。目标是开发新的方法来探测晶体和溶液中大分子的运动和随时间变化的结构变化，以阐明酶催化和生物信号事件的机制。我们的期望是，来自MacCHESS研究的结构-功能信息最终将突出新的治疗靶点，并有助于开发治疗疾病的临床策略。

DESCRIPTION (provided by applicant): Macromolecular Diffraction at the Cornell High Energy Synchrotron Source (MacCHESS) provides a facility for developing new technology and for advancing the research goals of structural biologists as well as the broader biological research community. MacCHESS also has a strong commitment to training future leaders, who will be able to translate advances in synchrotron science and structural biology into valuable biomedical applications. New Technology Research and Development projects (TR&Ds) by MacCHESS scientists will continue to be driven in the coming funding period by fundamentally important questions in biology and biomedicine (i.e., Driving Biomedical Projects or DBPs). The DBPs include investigations aimed at understanding complex membrane receptor-signaling systems, defining the regulation of ion channels in neuronal function, probing the catalytic mechanisms of enzymes playing central roles in key metabolic events, and delineating the complex macromolecular assemblies responsible for gene expression. When de-regulated, these processes can lead to the development of cancer and a number of other diseases. The TR&Ds being proposed to aid investigators in their efforts to address these important questions are: 1) Biological Small Angle X-ray Scattering (BioSAXS). New technology for the application of BioSAXS is being developed in response to increasing demands from the structural biology community to obtain information regarding the global conformational changes within macromolecular complexes (e.g. growth factor receptors, RNA-splicing complexes) and/or the changes in their oligomeric states that occur in solution and have important functional consequences. 2) Pressure Cryocooling. This unique MacCHESS technology offers exciting possibilities for trapping important protein conformational and enzymatic intermediate states that have not been previously solved, as well as facilitating structure determination from "difficult" crystals. 3) Multiple Small Crystals. Many membrane-associated complexes that are directly involved in hormone and growth factor-signaling events, as well as important neurotransmitter receptors and ion channels, give rise to crystals which are very small or diffract poorly. This project will enhance the ability to gain valuable structural information from such crystals. 4) Dynamics of Macromolecules. The goal is to develop new methods to probe macromolecular motions and time-dependent structural changes, both in crystals and in solution, to shed light on mechanisms of enzyme catalysis and biological signaling events. The expectation is that the structure-function information derived from research at MacCHESS will ultimately highlight novel therapeutic targets and aid in the development of clinical strategies for dealing with disease.