Structural basis of venom peptides that inhibit a Na+ channel regulator of pain

抑制疼痛 Na 通道调节剂的毒液肽的结构基础

• 批准号: 10415506
• 负责人: ASHLEE Hedgecock ROWE
• 金额: $ 15.13万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415506
• 关键词: Action Potentials; Aging; Arizona; Binding Sites; Biochemical; Biophysical Process; Biophysics; Brain; Centers of Research Excellence; Complex; Computer Models; Cryoelectron Microscopy; Disease; Docking; Drug Targeting; Engineering; Goals; Health system; Human; Injury; Knowledge; Link; Mediating; Membrane; Molecular; Mus; Natural Products; Neurons; Nociception; Oklahoma; Pain; Pain Disorder; Pathway interactions; Peptides; Pharmaceutical Preparations; Pore Proteins; Public Health; Scorpion Venoms; Scorpions; Signal Transduction; Sodium Channel; Structure; Venoms; base; chronic pain; inflammatory pain; opioid abuse; pain signal; painful neuropathy; spontaneous pain; structural biology; tool; transmission process; voltage

Chronic pain and opioid abuse cause human suffering and impose a burden on public health systems. A better understanding of the mechanisms that block transmission of pain signals would advance efforts to develop non-addictive pain drugs. Pain-pathway neurons transmit signals to the brain via action potentials. The voltage-gated sodium channel (VGSC) Nav1.8 is a protein pore that regulates the flux of Na+ across the membranes of nociceptive neurons, producing the action potentials that carry pain signals to the brain. Injury, aging and disease cause biochemical changes in neurons that activate Nav1.8 to initiate action potentials. Inactivation of Nav1.8 halts the transmission of pain signals. The mechanisms that govern inactivation provide a strategy for developing non-addictive pain drugs. Venom peptides from scorpions provide a toolkit for investigating inactivation mechanisms. For example, cryo-electron microscopy studies using scorpion peptides bound to Nav1.7, a channel responsible for spontaneous pain disorders, revealed the structural basis of fast inactivation. However, studying Nav1.8 inactivation mechanisms has proved challenging. While Nav1.8 has been linked to neuropathic and inflammatory pain, highlighting the potential for Nav1.8 to serve as an alternative drug target to Nav1.7, the mechanisms that regulate inactivation are not completely understood. Progress has been hindered by a lack of venom peptides that modify Nav1.8 gating. Arizona bark scorpion venom inhibits Nav1.8 and blocks pain in species of predatory mice. This study will use computational modeling to predict docking trajectories between inhibitory peptides and Nav1.8. The structural basis for peptide inhibition of Nav1.8 will be characterized by 1) mapping binding sites between peptides and the channel, and 2) building computational models of the peptide-Nav1.8 complex. Computational models of peptide-bound channels will reveal the structural basis for Nav1.8 gating. These goals are significant because inactivation is critical for regulating Nav1.8 activity and pain signal transmission. Knowledge of the biophysical and molecular bases for peptide-mediated inhibition of Nav1.8 would provide structural guides for engineering non-addictive pain drugs.

慢性疼痛和阿片类药物滥用会导致人类痛苦，并对公共卫生系统施加负担。一个 更好地理解阻止疼痛信号传播的机制 开发非疼痛药物。止痛道神经元通过动作电位向大脑传播信号。 电压门控钠通道（VGSC）NAV1.8是一种蛋白质孔，可调节Na+的通量跨度 伤害性神经元的膜，产生向大脑带来疼痛信号的动作电位。 损伤，衰老和疾病会导致神经元激活NAV1.8的生化变化 潜力。 NAV1.8的失活停止了疼痛信号的传播。控制机制 失活为开发非添加性疼痛药物提供了一种策略。灼热的毒肽 提供用于研究灭活机制的工具包。例如，冷冻电子显微镜研究 使用与NAV1.7结合的蝎子肽，该通道是自发疼痛障碍的通道 快速失活的结构基础。但是，研究NAV1.8灭活机制已证明 具有挑战性的。虽然NAV1.8已与神经性和炎症性疼痛联系起来，突出了潜力 为了使NAV1.8作为NAV1.7的替代药物靶标，调节失活的机制是 不完全理解。缺乏修饰nav1.8的毒液肽缺乏毒液的阻碍。 门控。亚利桑那州树皮蝎子毒液抑制NAV1.8，并阻止掠食性小鼠的疼痛。这 研究将使用计算建模来预测抑制性肽和 NAV1.8。 NAV1.8的肽抑制的结构基础将以1）映射结合为特征 肽和通道之间的位点，以及2）构建肽-NAV1.8的计算模型 复杂的。肽结合通道的计算模型将揭示NAV1.8的结构基础 门控。这些目标很重要，因为灭活对于调节NAV1.8活动和痛苦至关重要 信号传输。了解肽介导的抑制的生物物理和分子碱基的知识 NAV1.8将为工程非成瘾性止痛药提供结构指南。