Structure and Function of CB2 Cannabinoid Receptor

CB2 大麻素受体的结构和功能

• 批准号: 7440803
• 负责人: ZHAO-HUI SONG
• 金额: $ 4.04万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7440803
• 关键词: Absence of pain sensation; Adverse effects; Affinity; Affinity Chromatography; Agonist; Agreement; Amino Acids; Analgesics; Arts; Autoimmune Diseases; Binding; Biochemical; Biogenic Amine Receptors; CNR2 gene; Cannabinoids; Cellular biology; Characteristics; Chemicals; Class; Cloning; Collaborations; Condition; Conserved Sequence; Cysteine; Decompression Sickness; Development; Disulfide Linkage; Disulfides; Dopamine D2 Receptor; Ensure; Ethers; Ethyl Ether; Exhibits; Family; Fingerprint; Fluorescence Spectroscopy; Future; G-Protein-Coupled Receptors; Glaucoma; Goals; Growth; Helix (Snails); Hydrogen Bonding; Hydroxyl Radical; Immune; Immune system; Immunologic Receptors; Inflammation; Ions; Ligand Binding; Ligands; Liquid Chromatography; Maps; Marijuana; Mass Spectrum Analysis; Medical; Metals; Methodology; Methods; Modeling; Modification; Molecular; Molecular Biology; Molecular Conformation; Mutagenesis; Mutation; Nature; Neuraxis; Nuclear Magnetic Resonance; Numbers; Peptide Fragments; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacology; Pichia; Positioning Attribute; Post-Translational Protein Processing; Procedures; Process; Production; Proline; Property; Protein Chemistry; Protein Overexpression; Proteins; Proteomics; Purpose; Receptor Activation; Research Design; Research Personnel; Research Proposals; Resolution; Rhodopsin; Running; Site; Source; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure; Surface; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Transmembrane Domain; Work; X-Ray Crystallography; Yeasts; base; cannabinoid receptor; design; disulfide bond; ear helix; improved; insight; mimetics; molecular modeling; novel; programs; protein aminoacid sequence; protein structure; receptor; receptor structure function; scale up; tool

The long-term goal of this research proposal is to identify the molecular basis underlying the functions of the CB2 cannabinoid receptor. To achieve this purpose, the following steps will be taken. In Aim 1 and 2, the interactive mutagenesis, molecular modeling and new compound testing studies will be carried out. This combined approach has advanced our understanding, and should continue to reveal new insights on how cannabinoid ligands are recognized by their receptors, the origin of receptor subtype-selectivity, and how _these receptors are activated/inactivated. Cannabinoid receptors share many of the conserved sequence motifs seen in other well-studied G protein-coupled receptors (GPCRs), such as rhodopsin and biogenic amine receptors. However, several helix-bending residues and motifs, and a key disulfide bridge present in many other GPCRs are missing in cannabinoid receptors. In Aim 3, Ligand binding crevice exposure of two transmembrane domains of CB2 cannabinoid receptor will be mapped using substituted-cysteine accessibility method. This approach should elucidate structural and functional consequences of the sequence divergence in these trasmembrane domains of cannabinoid receptors. In Aim 4, Disulfide bond formation of CB2 receptor will be determined directly by the state-of-art methodologies of mass spectrometry. Investigating the unique disulfide bond or absence of a disulfide bond should provide important helix folding information of CB2 receptor, and this will have important implications regarding ligand binding crevice and activation mechanisms of this receptor. Finally, in Aim 5, effort will be devoted to over-express and purify large amounts of functional CB2 receptor. This challenging task, if successfully completed, should have a significant impact by providing the badly needed pure receptor proteins for future high-resolution biophysical studies. Overall, This study should help us to understand in more molecular detail the structure and function of CB2 receptor. CB2 is primarily distributed in the immune system. It is very important for the immune-modulatory effects of marijuana. In the long run, this study should also help us to develop better cannabinoid mimetics for the treatment of immune system illnesses, such as inflammation and autoimmune diseases. The drugs that soecifi(;allv taroeted at CB2 should be devoid of [}svchoactive side effects of marijuana.

这项研究计划的长期目标是确定潜在的功能的分子基础