A Distinct Functional Site in Ω-Neurotoxins: Novel Antagonists of Nicotinic Acetylcholine Receptors from Snake Venom

蛇毒 毒液 烟碱激动剂 乙酰胆碱受体 受体 乙酰胆碱 生物 烟碱乙酰胆碱受体 神经毒素 神经科学 药理学 生物化学
作者
Varuna Hassan‐Puttaswamy,David J. Adams,R. Manjunatha Kini
出处
期刊:ACS Chemical Biology [American Chemical Society]
卷期号:10 (12): 2805-2815 被引量:20
标识
DOI:10.1021/acschembio.5b00492
摘要

Snake venom α-neurotoxins from the three-finger toxin (3FTx) family are competitive antagonists with nanomolar affinity and high selectivity for nicotinic acetylcholine receptors (nAChR). Here, we report the characterization of a new group of competitive nAChR antagonists: Ω-neurotoxins. Although they belong to the 3FTx family, the characteristic functional residues of α-neurotoxins are not conserved. We evaluated the subtype specificity and structure-function relationships of Oh9-1, an Ω-neurotoxin from Ophiophagus hannah venom. Recombinant Oh9-1 showed reversible postsynaptic neurotoxicity in the micromolar range. Experiments with different nAChR subtypes expressed in Xenopus oocytes indicated Oh9-1 is selective for rat muscle type α1β1εδ (adult) and α1β1γδ (fetal) and rat neuronal α3β2 subtypes. However, Oh9-1 showed low or no affinity for other human and rat neuronal subtypes. Twelve individual alanine-scan mutants encompassing all three loops of Oh9-1 were evaluated for binding to α1β1εδ and α3β2 subtypes. Oh9-1's loop-II residues (M25, F27) were the most critical for interactions and formed the common binding core. Mutations at T23 and F26 caused a significant loss in activity at α1β1εδ receptors but had no effect on the interaction with the α3β2 subtype. Similarly, mutations at loop-II (H7, K22, H30) and -III (K45) of Oh9-1 had a distinctly different impact on its activity with these subtypes. Thus, Oh9-1 interacts with these nAChRs via distinct residues. Unlike α-neurotoxins, the tip of loop-II is not involved. We reveal a novel mode of interaction, where both sides of the β-strand of Oh9-1's loop-II interact with α1β1εδ, but only one side interacts with α3β2. Phylogenetic analysis revealed functional organization of the Ω-neurotoxins independent of α-neurotoxins. Thus, Ω-neurotoxin: Oh9-1 may be a new, structurally distinct class of 3FTxs that, like α-neurotoxins, antagonize nAChRs. However, Oh9-1 binds to the ACh binding pocket via a different set of functional residues.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
Tjh发布了新的文献求助10
刚刚
了吧完成签到,获得积分10
1秒前
2秒前
treasure23发布了新的文献求助10
2秒前
CBaeky完成签到,获得积分10
2秒前
垃圾桶完成签到 ,获得积分10
3秒前
NexusExplorer应助TT采纳,获得10
5秒前
小殷发布了新的文献求助10
6秒前
梨理栗完成签到,获得积分10
7秒前
小刚完成签到,获得积分0
7秒前
7秒前
zz完成签到,获得积分10
7秒前
9秒前
Akim应助小殷采纳,获得10
9秒前
英姑应助Lee采纳,获得10
10秒前
13秒前
肖竺筠完成签到,获得积分10
13秒前
tingtingzhang发布了新的文献求助10
14秒前
hdq发布了新的文献求助10
15秒前
16秒前
YJH完成签到,获得积分10
16秒前
16秒前
anzi发布了新的文献求助10
17秒前
QP34完成签到 ,获得积分10
17秒前
活力珠发布了新的文献求助10
18秒前
小忙完成签到 ,获得积分10
19秒前
20秒前
科研通AI2S应助正宗采纳,获得10
20秒前
20秒前
追光少年发布了新的文献求助10
21秒前
21秒前
Endless发布了新的文献求助10
22秒前
Lee发布了新的文献求助10
22秒前
23秒前
23秒前
流星雨完成签到,获得积分10
24秒前
林林完成签到,获得积分10
24秒前
幸福鸿发布了新的文献求助10
25秒前
orixero应助stone采纳,获得10
26秒前
llhh2024发布了新的文献求助10
26秒前
高分求助中
One Man Talking: Selected Essays of Shao Xunmei, 1929–1939 1000
A Chronicle of Small Beer: The Memoirs of Nan Green 1000
From Rural China to the Ivy League: Reminiscences of Transformations in Modern Chinese History 900
Eric Dunning and the Sociology of Sport 850
QMS18Ed2 | process management. 2nd ed 800
Operative Techniques in Pediatric Orthopaedic Surgery 510
The Making of Détente: Eastern Europe and Western Europe in the Cold War, 1965-75 500
热门求助领域 (近24小时)
化学 医学 材料科学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 物理化学 催化作用 免疫学 细胞生物学 电极
热门帖子
关注 科研通微信公众号,转发送积分 2914834
求助须知:如何正确求助?哪些是违规求助? 2552677
关于积分的说明 6907133
捐赠科研通 2214863
什么是DOI,文献DOI怎么找? 1177294
版权声明 588330
科研通“疑难数据库(出版商)”最低求助积分说明 576353