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μ-芋螺毒素GIIIA的个别二硫键在抑制Na1.4中的作用

The Role of Individual Disulfide Bonds of μ-Conotoxin GIIIA in the Inhibition of Na1.4.

作者信息

Han Penggang, Wang Kang, Dai Xiandong, Cao Ying, Liu Shangyi, Jiang Hui, Fan Chongxu, Wu Wenjian, Chen Jisheng

机构信息

College of Science, National University of Defense Technology, Changsha 410073, Hunan, China.

Beijing Institute of Pharmaceutical Chemistry, Beijing 102205, China.

出版信息

Mar Drugs. 2016 Nov 18;14(11):213. doi: 10.3390/md14110213.

DOI:10.3390/md14110213
PMID:27869701
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5128756/
Abstract

μ-Conotoxin GIIIA, a peptide toxin isolated from , preferentially blocks the skeletal muscle sodium channel Na1.4. GIIIA folds compactly to a pyramidal structure stabilized by three disulfide bonds. To assess the contributions of individual disulfide bonds of GIIIA to the blockade of Na1.4, seven disulfide-deficient analogues were prepared and characterized, each with one, two, or three pairs of disulfide-bonded Cys residues replaced with Ala. The inhibitory potency of the analogues against Na1.4 was assayed by whole cell patch-clamp on rNa1.4, heterologously expressed in HEK293 cells. The corresponding IC values were 0.069 ± 0.005 μM for GIIIA, 2.1 ± 0.3 μM for GIIIA-1, 3.3 ± 0.2 μM for GIIIA-2, and 15.8 ± 0.8 μM for GIIIA-3 (-1, -2 and -3 represent the removal of disulfide bridges Cys3-Cys15, Cys4-Cys20 and Cys10-Cys21, respectively). Other analogues were not active enough for IC measurement. Our results indicate that all three disulfide bonds of GIIIA are required to produce effective inhibition of Na1.4, and the removal of any one significantly lowers its sodium channel binding affinity. Cys10-Cys21 is the most important for the Na1.4 potency.

摘要

μ-芋螺毒素GIIIA是一种从[具体来源未给出]分离出的肽毒素，它优先阻断骨骼肌钠通道Na1.4。GIIIA紧密折叠成由三个二硫键稳定的金字塔结构。为了评估GIIIA中各个二硫键对Na1.4阻断作用的贡献，制备并表征了七种缺乏二硫键的类似物，每种类似物都有一对、两对或三对二硫键连接的半胱氨酸残基被丙氨酸取代。通过在HEK293细胞中异源表达的rNa1.4上进行全细胞膜片钳实验，测定了这些类似物对Na1.4的抑制效力。GIIIA的相应IC值为0.069±0.005μM，GIIIA-1为2.1±0.3μM，GIIIA-2为3.3±0.2μM，GIIIA-3为15.8±0.8μM（-1、-2和-3分别代表去除二硫键Cys3-Cys15、Cys4-Cys20和Cys10-Cys21）。其他类似物的活性不足以进行IC测量。我们的结果表明，GIIIA的所有三个二硫键都是产生对Na1.4有效抑制所必需的，去除任何一个都会显著降低其与钠通道的结合亲和力。Cys10-Cys21对Na1.4的效力最为重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/f365104d5cab/marinedrugs-14-00213-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/fcbfb9afec45/marinedrugs-14-00213-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/0b020181d19d/marinedrugs-14-00213-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/dbc5ffd561ac/marinedrugs-14-00213-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/c06a5fbd6314/marinedrugs-14-00213-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/f365104d5cab/marinedrugs-14-00213-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/fcbfb9afec45/marinedrugs-14-00213-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/0b020181d19d/marinedrugs-14-00213-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/dbc5ffd561ac/marinedrugs-14-00213-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/c06a5fbd6314/marinedrugs-14-00213-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf6/5128756/f365104d5cab/marinedrugs-14-00213-g005.jpg

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