Structural studies of CaV alpha2delta subunits and interaction with anti-nocicept

CaV α2δ 亚基的结构研究及其与抗伤害感受剂的相互作用

• 批准号: 7918001
• 负责人: DANIEL L MINOR
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918001
• 关键词: Affect; Architecture; Binding; Biochemical; Calcium Channel; Complex; Crystallization; Development; Drug usage; Epilepsy; Extracellular Domain; FDA approved; Fibromyalgia; Knowledge; Migraine; Molecular; Molecular Structure; Mood Disorders; Nervous system structure; Pain; Pain Disorder; Pharmaceutical Preparations; Population; Property; Proteins; Research; Resolution; Roentgen Rays; Site; Structure; System; Therapeutic; Ursidae Family; Woman; Work; chronic pain; extracellular; gabapentin; improved; nervous system disorder; overexpression; painful neuropathy; pregabalin; public health relevance; therapy development; three dimensional structure; voltage

DESCRIPTION (provided by applicant): The voltage-gated calcium channel CaVa2d subunit is the site of action of two gabapentinoid drugs, gabapentin (Neurontin) and pregabalin (Lyrica), that are used to treat neuropathic pain, pain associated with fibromyaglia, migraine, epilepsy, and a number of mood disorders. Despite the direct connection between CaVa2d and the treatment of nervous system disorders, nothing is known about CaVa2d molecular structure at high resolution, the detailed molecular mechanisms by which CaVa2d affects voltage-gated calcium channel function, or how gabapentin and pregabalin bind to CaVa2d and modulate voltage-gated calcium channel activity. We seek to determine the high-resolution structure of CaVa2d and CaVa2d complexes with gabapentinoid drugs. Our efforts are directed at developing the appropriate expression systems to produce CaVa2d proteins for crystallographic study and to solve the high-resolution structure of CaVa2d. This work should unveil the fundamental structures that underlie CaVa2d function and reveal how gabapentinoid drugs interact with CaVa2d. This knowledge will bear directly on understanding the basic mechanisms of action of gabapentinoid drugs and should facilitate the development of better therapeutics that will improve the treatment of pain and a wide range of nervous system and mood disorders. PUBLIC HEALTH RELEVANCE: Voltage-gated calcium channels are the targets of drugs that are used to treat pain, epilepsy, migraine, fibromyalgia, and mood disorders. Our work aims to determine the molecular architecture that underlies how such drugs interact with and affect channel function. Such knowledge is indispensable for the improvement of current therapies and development of more efficacious treatments for a variety of nervous system disorders.

描述（由申请人提供）：电压门控钙通道CaVa2d亚基是两种加巴喷丁类药物加巴喷丁（Neurontin）和普瑞巴林（Lyrica）的作用部位，用于治疗神经性疼痛、与纤维肌痛相关的疼痛、偏头痛、癫痫和许多情绪障碍。尽管CaVa2d与 和神经系统疾病的治疗，关于高分辨率的CaVa 2d分子结构、CaVa 2d影响电压门控钙通道功能的详细分子机制、或加巴喷丁和普瑞巴林如何结合CaVa 2d并调节电压门控钙通道活性还一无所知。我们试图确定高分辨率的CaVa2d和CaVa2d与gabapentinoid药物的复合物的结构。我们的努力是针对发展适当的表达系统，以产生CaVa2d蛋白的晶体学研究，并解决高分辨率的结构CaVa2d。这项工作将揭示CaVa2d功能的基本结构，并揭示加巴喷丁类药物如何与CaVa2d相互作用。这些知识将直接影响对加巴喷丁类药物作用的基本机制的理解，并应促进更好的治疗方法的发展，这将改善疼痛和广泛的神经系统和情绪障碍的治疗。 公共卫生相关性：电压门控钙通道是用于治疗疼痛、癫痫、偏头痛、纤维肌痛和情绪障碍的药物的靶点。我们的工作旨在确定这些药物如何相互作用并影响通道功能的分子结构。这些知识对于改善目前的治疗方法和开发针对各种神经系统疾病的更有效的治疗方法是不可或缺的。