A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3.
A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3.
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DOI：
10.1371/journal.pbio.3002217
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发表时间：
2023-08
期刊：
影响因子：
9.8
通讯作者：
Ellgaard, Lars
中科院分区：
文献类型：
--
作者：
Hackney, Celeste D.;Salcedo, Paula Florez;Mueller, Emilie;Koch, Thomas Lund;Kjelgaard, Lau R.;Watkins, Maren J.;Zachariassen, Linda S.;Tuelund, Pernille Sonderby;McArthur, Jeffrey K.;Adams, David;Kristensen, Anders;Olivera, Baldomero;Finol-Urdaneta, Rocio;Safavi-Hemami, Helena;Morth, Jens Preben;Ellgaard, Lars
动物毒液肽是生物医学研究的重要化合物。海洋锥螺的毒液构成了一个特别丰富的肽毒素来源，称为芋螺毒素。在这里，我们确定了一个非常大的芋螺毒素，Mu8.1，它定义了一类新的芋螺毒素进化相关的众所周知的con-ikot-ikots和2个额外的芋螺毒素类以前没有描述的序列。重组Mu8.1的晶体结构显示saposin样折叠，并显示与con-ikot-ikot的结构相似性。功能研究表明，Mu8.1在确定类别的小鼠体感背根神经节（DRG）神经元中减少钙内流。当在多种重组表达的电压门控离子通道上测试时，Mu8.1显示出对R型（Cav2.3）钙通道的最高效力。来自Mu8.1敏感DRG神经元的Ca 2+信号也被SNX-482抑制，SNX-482是Cav2.3和电压门控K+（Kv 4）通道的已知蜘蛛肽调节剂。我们的研究结果突出了Mu8.1作为分子工具来识别和研究表达Cav2.3的神经元亚类的潜力。重要的是，这项多学科研究展示了在大部分未开发的巨型芋螺毒素组中发现新结构和生物活性的潜力。动物毒液肽代表了生物医学探索的有价值的化合物，包括来自海洋锥螺的芋螺毒素。在这项研究中，以前未被识别的大芋螺毒素超家族的鉴定揭示了抑制神经元Cav2.3电压门控钙通道的毒素的结构和进化见解。
Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins. Animal venom peptides represent valuable compounds for biomedical exploration, including conotoxins from marine cone snails. In this study, the identification of a previously unrecognized superfamily of large conotoxins reveals structural and evolutionary insight into a toxin that inhibits neuronal Cav2.3 voltage-gated calcium channels.
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影响因子：
6.4
作者：
Hatahet F;Nguyen VD;Salo KE;Ruddock LW
通讯作者：
Ruddock LW
影响因子：
4.8
作者：
Craig, AG;Jimenez, EC;McIntosh, JM
通讯作者：
McIntosh, JM
DOI：
10.1085/jgp.202112912
发表时间：
2022-05-02
期刊：
The Journal of general physiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
2
作者：
Fang, Zhi;Hwang, Jae Hong;Oh, Seog Bae
通讯作者：
Oh, Seog Bae
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH