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给人类带来痛苦，并给公共卫生系统带来负担。一个 更好地了解阻止疼痛信号传输的机制将推动以下方面的努力： 开发非成瘾性止痛药。疼痛通路神经元通过动作电位将信号传输到大脑。 电压门控钠通道 (VGSC) Nav1.8 是一种蛋白质孔，可调节 Na+ 穿过通道的通量 伤害感受神经元的膜，产生将疼痛信号传递到大脑的动作电位。 损伤、衰老和疾病会导致神经元发生生化变化，从而激活 Nav1.8 启动行动 潜力。 Nav1.8 失活会停止疼痛信号的传输。治理机制 灭活为开发非成瘾性止痛药提供了一种策略。蝎子毒液肽 提供用于研究失活机制的工具包。例如，冷冻电子显微镜研究 使用与 Nav1.7 结合的蝎肽，Nav1.7 是导致自发性疼痛疾病的通道 快速失活的结构基础。然而，研究Nav1.8失活机制已经证明 具有挑战性的。虽然 Nav1.8 与神经性疼痛和炎症性疼痛有关，但这凸显了它的潜力 对于 Nav1.8 作为 Nav1.7 的替代药物靶点，调节失活的机制是 没有完全理解。由于缺乏修饰 Nav1.8 的毒液肽，进展受到阻碍 门控。亚利桑那树皮蝎毒液抑制 Nav1.8 并阻止掠食性小鼠的疼痛。这 研究将使用计算模型来预测抑制肽和 导航1.8。 Nav1.8 肽抑制的结构基础特征在于 1) 定位结合 肽和通道之间的位点，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。这些目标意义重大，因为失活对于调节 Nav1.8 活动和疼痛至关重要 信号传输。了解肽介导的抑制的生物物理和分子基础 Nav1.8 将为设计非成瘾性止痛药提供结构指南。