Structural Characterization of Gbetagamma-Phospholipase C complexes

Gbetagamma-磷脂酶 C 复合物的结构表征

• 批准号: 10389848
• 负责人: ISAAC FISHER
• 金额: $ 6.76万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389848
• 关键词: Absence of pain sensation; Address; Analgesics; Architecture; Binding; Binding Proteins; Binding Sites; Biological Assay; C-terminal; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cartoons; Cell membrane; Cells; Chemicals; Complex; Complex Analysis; Consensus; Cryoelectron Microscopy; Crystallization; Data; Deuterium; Development; Disease; Distal; EF Hand Motifs; Enzymes; Family; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Health; Healthcare; Heart Diseases; Heart Hypertrophy; Heterogeneity; Heterotrimeric G Protein Subunit; Human; Hydrogen; In Vitro; Lipase; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Membrane; Molecular; Molecular Conformation; Mutagenesis; Opioid; Opioid Analgesics; PH Domain; Pathology; Pathway interactions; Phosphatidylinositol 4,5-Diphosphate; Phospholipase; Phospholipase C; Physiology; Pre-Clinical Model; Process; Protein Isoforms; Protein Kinase C; Proteins; Regulation; Research; Resolution; Roentgen Rays; Role; Second Messenger Systems; Signal Transduction; Site-Directed Mutagenesis; Structure; Sulfhydryl Compounds; Surface; Testing; Therapeutic; United States; base; crosslink; improved outcome; insight; mutant; non-opioid analgesic; novel; opioid epidemic; particle; prevent; protein protein interaction; protein structure; reconstruction; response; therapeutic target; tool; treatment strategy

PROJECT SUMMARY The opioid crisis, cardiovascular disease, and cancer are the most pressing healthcare crises in the United States. PLCβ enzymes are essential for normal analgesic, cardiovascular, and proliferative signaling. Further, disruption of interactions between PLCβ and its G protein activators have been shown to improve outcomes in preclinical models of opioid induced analgesia, cardiac hypertrophy, and cancer. However, targeting these interactions specifically is nearly impossible in the absence of structural data that informs on the conformational differences between inactive, active, and G protein bound PLCβ states. The goal of this project is to understand mechanisms of PLCβ activation by Gβγ and/or the membrane through structural and functional studies. The Gβγ binding site on PLCβ has yet to be defined, and overall, Gβγ- dependent regulation of effector enzymes is a poorly understood process. This project would not only increase our overall understanding of PLCβ signaling at the membrane and in conjunction with Gβγ but would also provide insights into the regulation of other enzymes that act at the membrane interface. The completion of this study will synergistically increase our understanding of PLCβ activation mechanisms, providing insights that can be leveraged for the development of probes, and ultimately potential therapeutics, targeting G protein–PLCβ interactions.

项目摘要 阿片类药物危机，心血管疾病和癌症是紧迫的医疗危机 联合plcββ酶对于正常，心血管和 进一步的信号传导。 已经证明激活剂可以改善阿片类药物诱导的临床前模型 但是，针对相互作用的肛门，心脏肥大和癌症 在缺乏信息差异的结构数据的情况下，几乎不可能 在不活跃，活性和G蛋白结合的PLCβ态之间。 了解通过结构和/或通过结构和/或 功能研究。 酶的量角调节是 仅提高我们对膜和结合处PLCβ信号传导的理解 使用Gβγ，但也将深入了解作用于对 膜接口。 PLCβ激活机制，提供可以利用的见解 探针以及最终靶向G蛋白 - PLCβ相互作用的探针。