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

慢性疼痛和阿片类药物滥用造成人类痛苦，并给公共卫生系统带来负担。一 更好地了解阻断疼痛信号传递的机制将有助于 开发非成瘾性止痛药疼痛通路神经元通过动作电位向大脑传递信号。 电压门控钠通道（VGSC）Nav1.8是一种蛋白质孔，其调节Na+跨膜的通量。 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、衰老和疾病导致神经元发生生化变化，激活Nav1.8启动行动 潜力Nav1.8的失活会阻止疼痛信号的传递。管理的机制 失活提供了一种开发非成瘾性止痛药策略。蝎毒肽 为研究失活机制提供了一个工具包。例如，冷冻电子显微镜研究 利用与Nav1.7（一种负责自发性疼痛障碍的通道）结合的蝎子肽， 快速失活的结构基础。然而，研究Nav1.8失活机制已经证明， 挑战性虽然Nav1.8与神经性和炎症性疼痛有关，但强调了其潜在的 对于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。由于缺乏修饰Nav1.8的毒液肽，进展受到阻碍。 门控亚利桑那州树皮蝎毒液抑制Nav1.8并阻止捕食性小鼠的疼痛。这 这项研究将使用计算机建模来预测抑制肽之间的对接轨迹， 导航1.8。Nav1.8的肽抑制的结构基础将通过以下来表征：1）绘制结合图 肽和通道之间的位点，以及2）建立肽-Nav 1.8的计算模型 复杂.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活性和疼痛至关重要 信号传输肽介导的抑制的生物物理和分子基础的知识， Nav1.8将为非成瘾性止痛药的工程设计提供结构指导。

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.