Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences.
Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences.
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DOI：
10.1038/srep37460
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发表时间：
2016-11-22
影响因子：
4.6
通讯作者：
Tominaga M
中科院分区：
文献类型：
--
作者：
Gupta R;Saito S;Mori Y;Itoh SG;Okumura H;Tominaga M
疼痛是由有害刺激引起的有害感觉。瞬时受体电位锚蛋白1（TRPA 1）是研究疼痛机制的一个靶标。TRPA 1被各种刺激物激活，如有害的寒冷，刺激性天然产物和环境刺激物。由于TRPA 1是疼痛治疗的有吸引力的靶标，已经开发了一些TRPA 1拮抗剂，并且一些用作镇痛剂。TRPA 1对激动剂和拮抗剂的反应在物种之间不同，这些物种差异已被用于识别激活和抑制机制的结构基础。TRPA 1拮抗剂HC-030031（HC）不能抑制由肉桂醛（CA）诱导的青蛙TRPA 1（fTRPA 1）和斑马鱼TRPA 1活性，但在异源表达系统中抑制人TRPA 1（hTRPA 1）。fTRPA 1和hTRPA 1之间的嵌合研究以及使用点突变体的分析显示，单个氨基酸残基（hTRPA 1中的N855）显著有助于HC的抑制作用。此外，N855残基和C-末端区域表现出协同效应的抑制HC。分子动力学模拟表明HC与hTRPA 1-N855稳定结合。这些发现为TRPA 1的结构-功能关系提供了新的见解，并可能导致开发针对TRPA 1的更有效的镇痛药。
Pain is a harmful sensation that arises from noxious stimuli. Transient receptor potential ankyrin 1 (TRPA1) is one target for studying pain mechanisms. TRPA1 is activated by various stimuli such as noxious cold, pungent natural products and environmental irritants. Since TRPA1 is an attractive target for pain therapy, a few TRPA1 antagonists have been developed and some function as analgesic agents. The responses of TRPA1 to agonists and antagonists vary among species and these species differences have been utilized to identify the structural basis of activation and inhibition mechanisms. The TRPA1 antagonist HC-030031 (HC) failed to inhibit frog TRPA1 (fTRPA1) and zebrafish TRPA1 activity induced by cinnamaldehyde (CA), but did inhibit human TRPA1 (hTRPA1) in a heterologous expression system. Chimeric studies between fTRPA1 and hTRPA1, as well as analyses using point mutants, revealed that a single amino acid residue (N855 in hTRPA1) significantly contributes to the inhibitory action of HC. Moreover, the N855 residue and the C-terminus region exhibited synergistic effects on the inhibition by HC. Molecular dynamics simulation suggested that HC stably binds to hTRPA1-N855. These findings provide novel insights into the structure-function relationship of TRPA1 and could lead to the development of more effective analgesics targeted to TRPA1.
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影响因子：
3.4
作者：
Nagatomo, Katsuhiro;Ishii, Hiroshi;Kubo, Yoshihiro
通讯作者：
Kubo, Yoshihiro
影响因子：
3.3
作者：
Cavanaugh, E. J.;Simkin, D.;Kim, D.
通讯作者：
Kim, D.
影响因子：
2.9
作者：
HOOVER, WG
通讯作者：
HOOVER, WG
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
DOI：
10.1085/jgp.200810138
发表时间：
2009-03
期刊：
The Journal of general physiology
影响因子：
--
作者：
Bang S;Hwang SW
通讯作者：
Hwang SW