MEDIC - MicroED Imaging Center - Driving Biomedical Projects (DBPs)

MEDIC - MicroED 成像中心 - 推动生物医学项目 (DBP)

• 批准号: 10641832
• 负责人: Tamir Gonen
• 金额: $ 10.93万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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/10641832
• 关键词: Address; Affect; Antibodies; Automobile Driving; Biochemistry; Biomedical Research; Capsid Proteins; Charge; Chemistry; Communication; Complex; Cryoelectron Microscopy; Crystallization; DNA; Development; Drug Targeting; Electron Diffraction Microscopy; Family; G-Protein-Coupled Receptors; Gene Expression; HIV-1; Ligands; Medicine; Membrane Proteins; Membrane Transport Proteins; Molecular Conformation; Natural Products; Nutrient; Porosity; Proteins; Regulation; Resolution; Structure; Technology; X-Ray Crystallography; drug discovery; electron diffraction; experience; imaging facilities; interest; neurotransmission; protein complex; protein function; protein structure; protonation; receptor; research and development; small molecule; structural biology; symporter; technology development

Driving Biomedical Projects (DBPs) Summary We selected the Driving Biomedical Projects (DBPs) for this proposal to encompass the forefront in biomedical research and cover the US from coast to coast. Some of the most fundamental questions in biochemistry are being addressed using microcrystal electron diffraction (MicroED): How do ligands regulate the structure and function of G-protein coupled receptors? (Lefkowitz, Stevens); What are the conformational dynamics that are involved in substrate recognition and transport in the largest family of membrane transporters? (Abramson, Zheng); Structural biology of large porous protein complexes that are involved in neurotransmission and fusion (Hurley); The protonation and charged state in membrane proteins and how those affect protein function (Rees, Yeager); How proteins are recognized by antibodies and how proteins can regulate gene expression (Bjorkman, Feigon); and the utility of MicroED in understanding and discovery of natural products (van der Donk). We chose to focus our efforts on the study of natural products, protein complexes and of membrane proteins because these are extremely challenging and yet very important targets for drug discovery and medicine. The interactions with the DBPs will be supervised by Dr. Gonen, who has more than 20 years' experience working with membrane proteins of different kinds, including, channels, transporters and receptors and has determined several key membrane protein structures by cryoEM and X-ray crystallography. Moreover, he holds a degree in Chemistry which allows him to effectively communicate with chemists and biologists alike. Many of the DBP targets are hard to express, purify and crystallize. By applying MicroED we help to alleviate these difficulties; when a membrane protein of interest if expressed in low amounts, the resulting material may still be sufficient for structure determination by MicroED. Finally, MicroED can deliver atomic resolution structures from femtogram amounts of small molecules and natural products without additional purification and crystallization . All DBPs benefit from the Technology and Research Development projects of this application and are good testbeds for them. They are also excellent vehicles for dissemination of MicroED technology.

推动生物医学项目 (DBP) 概括 我们为此提案选择了驱动生物医学项目 (DBP)，以涵盖生物医学领域的最前沿 研究并覆盖美国从东海岸到西海岸。生物化学中一些最基本的问题是 正在使用微晶电子衍射（MicroED）解决：配体如何调节结构和 G蛋白偶联受体的功能？ （史蒂文斯·莱夫科维茨）；构象动力学是什么 参与最大的膜转运蛋白家族中的底物识别和转运？ （艾布拉姆森， 郑）；参与神经传递和融合的大型多孔蛋白质复合物的结构生物学 （赫尔利）；膜蛋白的质子化和带电状态以及它们如何影响蛋白质功能（Rees， 耶格尔）；蛋白质如何被抗体识别以及蛋白质如何调节基因表达（Bjorkman， 费贡）；以及 MicroED 在理解和发现天然产物方面的效用 (van der Donk)。我们选择了 将我们的努力集中在天然产物、蛋白质复合物和膜蛋白的研究上，因为这些 对于药物发现和医学来说极具挑战性但又非常重要的目标。与的相互作用 DBP 将由拥有 20 多年膜工作经验的 Gonen 博士监督 不同种类的蛋白质，包括通道、转运蛋白和受体，并确定了几个关键的 通过冷冻电镜和 X 射线晶体学分析膜蛋白结构。此外，他还拥有化学学位 这使他能够与化学家和生物学家等进行有效的沟通。许多 DBP 目标是 难以表达、纯化和结晶。通过应用 MicroED，我们可以帮助缓解这些困难；当一个 感兴趣的膜蛋白如果表达量较低，所得材料可能仍足以用于 通过 MicroED 确定结构。最后，MicroED 可以从飞克级提供原子分辨率结构 大量的小分子和天然产物，无需额外纯化和结晶。所有 DBP 受益于该应用程序的技术和研究开发项目，并且是良好的测试平台 他们。它们也是传播 MicroED 技术的优秀工具。