Macromolecular Diffraction Resource: MacCHESS

描述（由申请人提供）：康奈尔高能同步加速器源（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界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与开发项目（TR&Ds）将在即将到来的资助期内继续受到生物学和生物医学领域根本性重要问题的推动（即驱动生物医学项目或dbp）。dbp包括旨在理解复杂膜受体信号系统的研究，定义神经元功能中离子通道的调节，探测在关键代谢事件中起核心作用的酶的催化机制，以及描述负责基因表达的复杂大分子组装。当不受控制时，这些过程会导致癌症和许多其他疾病的发展。为了帮助研究人员解决这些重要问题而提出的tr&d是：1)生物小角度x射线散射（BioSAXS）。为了满足结构生物学界对获取大分子复合物（如生长因子受体、rna剪接复合物）内全局构象变化和/或溶液中发生的具有重要功能后果的寡聚物状态变化的信息的日益增长的需求，正在开发用于BioSAXS应用的新技术。2)压力冷冻。这种独特的MacCHESS技术为捕获重要的蛋白质构象和酶的中间状态提供了令人兴奋的可能性，这些状态以前没有被解决，以及促进从“困难”晶体中确定结构。3)多个小晶体。许多直接参与激素和生长因子信号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，产生非常小或衍射能力差的晶体。这个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的大分子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。期望从MacCHESS的研究中获得的结构-功能信息将最终突出新的治疗靶点，并有助于治疗疾病的临床策略的发展。

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.