INTERACTIONS OF A NOVEL LIGAND WITH A MODEL CHANNEL

新型配体与模型通道的相互作用

• 批准号: 2701779
• 负责人: KI-JOON SHON
• 金额: $ 10.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2701779
• 关键词: Gastropoda; Torpedo; acetylcholine; animal tissue; chemical binding; chemical models; chemical synthesis; crosslink; fish electric organ; high performance liquid chromatography; ligands; lipid bilayer membrane; membrane channels; membrane proteins; membrane structure; method development; neurotoxins; nicotinic receptors; nuclear magnetic resonance spectroscopy; protein structure; radiotracer; receptor binding

Membrane associated receptors and ion channels serve as the molecular basis for electrical signaling, selective information transfer between excitable cells, and controlling the activity of the nervous system. Contrary to their biological significance, very little is known about how these proteins recognize neurotransmitters and ligands at the molecular level. The PI is interested in developing a novel methodology for revealing molecular features governing ligand-receptor recognition using modern high- field NMR spectroscopy. The methodology focuses on 1) designing relatively small model systems for ligand-receptor complexes, 2) developing a chemical strategy for synthesizing such models in the case of ion channels, the ability to transport ions is retained, and 3) applying both solution and solid-state NMR techniques to free ligands in aqueous solution, model channels in detergent micelles, and ligand-receptor complexes in lipids. Conotoxins, peptide neurotoxins from Conus snails, are ideal molecules for providing a model system for studying ligand-receptor interactions. They bind these membrane proteins with dissociation constants in nanomolar range, and there are potentially tens of thousands of these peptide ligands. The proposed project is based on exploiting their extraordinary specificity in developing model systems suitable for structural studies by NMR methods. A novel ligand (psi-conotoxin), which is a non-competitive inhibitor of the nicotinic acetylcholine receptor, has been recently discovered by the PI. The present experimental evidence strongly suggests that the binding region is at the carboxyl ends of the second transmembrane domains (M2). Such model channel has been chemically synthesized, and structure determination of the channel and its ligand bound complex will be the main focus of this proposal. Successful execution of the research will provide leads for rational drug design as well as for engineering subtype specific ligands targeted to specific receptors and ion channels.

膜相关受体和离子通道是分子基础