Allosteric Regulation of GPCRs

GPCR 的变构调节

基本信息

批准号：
8731955
负责人：
Roger K Sunahara
金额：
$ 31.45万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8731955
关键词：
Accounting Affinity Agonist Allosteric Regulation Arrestins Binding Biochemical Biological Assay Biological Models Biological Testing Biology Cells Cellular Assay Collaborations Contracts Coupling Data Dimerization Endowment Engineering Face G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Goals Hormones Human Genome Project Instruction Laboratories Ligand Binding Ligands Lipids Malignant Neoplasms Measures Molecular Conformation Opioid Opioid Receptor Outcome Pathology Pathway interactions Peptides Pharmaceutical Preparations Preparation Property Protein Binding Protein Isoforms Proteins Protomer Research Personnel Signal Pathway Signal Transduction Site Specificity Stimulus Structure Therapeutic Translating Transmembrane Domain Work base design dimer extracellular insight intercellular communication interest mouse model mutant novel novel strategies novel therapeutics protein activation receptor receptor function screening small molecule therapeutic target tool virtual

项目摘要

PROJECT SUMMARY (See instructions): Our major goal is to study the basis of ligand recognition by GPCRs and determine how orthosteric and allosteric ligands stabilize specific receptor conformations. Together with Project 1 and 3 we will attempt to understand how ligands discriminate not only between different receptor types but to determine how they discriminate between active and inactive conformations. These endeavors will take advantage of the structural data, biophysical and pharmacological analyses to both identify novel compounds that may help to discriminate receptor isoforms. We will take into consideration divergent regions that are not involved in orthosteric, hormone-binding interactions, including the extracellular and intracellular faces ofthe receptor. We will also target regions within the TM domains but outside the orthosteric site, such as the crevice identified in the p-opiate receptor (pOR) crystal structure, between the pOR protomers of the crystallized dimer. Thus, by utilizing regions outside the orthosteric site we may engineer more selectivity into ligands that could potentially be translated to novel therapeutics. We will study how agents (small molecules, peptides and proteins) bind to- and stabilize active and inactive conformations. We will work concurrently with Projects 1 (design) and 3 (structure) to study how ligands structures generated from virtual screening around active and inactive conformations participate may stabilize, or perhaps disrupt these states. We are particularly interested in agents which display cooperative, or allosteric, effects on the hormone binding, or orthosteric site. We will take advantage of our recent crystallographic efforts to understand the basis for G protein activation has offered some insights into how G proteins allosterically alter hormone (agonist) binding.

项目摘要（参见说明）：我们的主要目标是研究 GPCR 配体识别的基础，并确定正构和变构配体如何稳定特定受体构象。与项目 1 和 3 一起，我们将尝试了解配体不仅如何区分不同的受体类型，而且还确定它们如何区分活性和非活性构象。这些努力将利用结构数据、生物物理和药理学分析来鉴定可能有助于区分受体亚型的新化合物。我们将考虑不参与正位、激素结合相互作用的不同区域，包括受体的细胞外和细胞内表面。我们还将靶向 TM 结构域内但在正构位点之外的区域，例如在结晶二聚体的 pOR 原聚体之间的 p-阿片受体 (pOR) 晶体结构中识别的缝隙。因此，通过利用正位点之外的区域，我们可以设计出更多选择性的配体，从而有可能转化为新的治疗方法。我们将研究药物（小分子、肽和蛋白质）如何结合并稳定活性和非活性构象。我们将与项目 1（设计）和 3（结构）同时开展工作，研究通过围绕活性和非活性构象的虚拟筛选生成的配体结构如何稳定或破坏这些状态。我们对对激素结合或正构位点表现出协同或变构效应的药物特别感兴趣。我们将利用最近的晶体学努力来了解 G 蛋白激活的基础，这为 G 蛋白如何变构改变激素（激动剂）结合提供了一些见解。