Kvetkina Aleksandra N, Oreshkov Sergey D, Mironov Pavel A, Zaigraev Maxim M, Klimovich Anna A, Deriavko Yulia V, Menshov Aleksandr S, Kulbatskii Dmitrii S, Logashina Yulia A, Andreev Yaroslav A, Chugunov Anton O, Kirpichnikov Mikhail P, Lyukmanova Ekaterina N, Leychenko Elena V, Shenkarev Zakhar O
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 690022 Vladivostok, Russia.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 119997 Moscow, Russia.
Mar Drugs. 2024 Dec 2;22(12):542. doi: 10.3390/md22120542.
TRPA1 is a homotetrameric non-selective calcium-permeable channel. It contributes to chemical and temperature sensitivity, acute pain sensation, and development of inflammation. HCIQ2c1 is a peptide from the sea anemone that inhibits serine proteases. Here, we showed that HCIQ2c1 significantly reduces AITC- and capsaicin-induced pain and inflammation in mice. Electrophysiology recordings in oocytes expressing rat TRPA1 channel revealed that HCIQ2c1 binds to open TRPA1 and prevents its transition to closed and inhibitor-insensitive 'hyperactivated' states. NMR study of the N-labeled recombinant HCIQ2c1 analog described a classical Kunitz-type structure and revealed two dynamic hot-spots (loops responsible for protease binding and regions near the - and -termini) that exhibit simultaneous mobility on two timescales (ps-ns and μs-ms). In modelled HCIQ2c1/TRPA1 complex, the peptide interacts simultaneously with one voltage-sensing-like domain and two pore domain fragments from different channel's subunits, and with lipid molecules. The model explains stabilization of the channel in the open conformation and the restriction of 'hyperactivation', which are probably responsible for the observed analgetic activity. HCIQ2c1 is the third peptide ligand of TRPA1 from sea anemones and the first Kunitz-type ligand of this channel. HCIQ2c1 is a prototype of efficient analgesic and anti-inflammatory drugs.
瞬时受体电位锚蛋白1（TRPA1）是一种同源四聚体非选择性钙通透性通道。它与化学和温度敏感性、急性疼痛感觉以及炎症的发展有关。HCIQ2c1是一种来自海葵的肽，可抑制丝氨酸蛋白酶。在此，我们表明HCIQ2c1能显著减轻异硫氰酸烯丙酯（AITC）和辣椒素诱导的小鼠疼痛和炎症。对表达大鼠TRPA1通道的卵母细胞进行的电生理记录显示，HCIQ2c1与开放的TRPA1结合，并阻止其转变为关闭且对抑制剂不敏感的“超激活”状态。对N标记的重组HCIQ2c1类似物的核磁共振研究描述了一种经典的库尼茨型结构，并揭示了两个动态热点（负责蛋白酶结合的环以及靠近N端和C端的区域），它们在两个时间尺度（皮秒-纳秒和微秒-毫秒）上同时表现出流动性。在模拟的HCIQ2c1/TRPA1复合物中，该肽同时与一个电压感应样结构域以及来自不同通道亚基的两个孔道结构域片段相互作用，还与脂质分子相互作用。该模型解释了通道在开放构象中的稳定性以及“超激活”的受限，这可能是观察到的镇痛活性的原因。HCIQ2c1是来自海葵的TRPA1的第三种肽配体，也是该通道的首个库尼茨型配体。HCIQ2c1是高效镇痛和抗炎药物的原型。
