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首页> 外文期刊>Journal of Molecular Biology >alpha-RgIA, a novel conotoxin that blocks the alpha 9 alpha 10 nAChR: Structure and identification of key receptor-binding residues
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alpha-RgIA, a novel conotoxin that blocks the alpha 9 alpha 10 nAChR: Structure and identification of key receptor-binding residues

机译：alpha-RgIA，一种新型的毒素，可阻断α9 alpha 10 nAChR：关键受体结合残基的结构和鉴定

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摘要

alpha-Conotoxins are small disulfide-constrained peptides from cone snails that act as antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). The 13-residue peptide alpha-conotoxin RgIA (alpha-RgIA) is a member of the alpha-4,3 family of alpha-conotoxins and selectively blocks the alpha 9 alpha 10 nAChR subtype, in contrast to another well-characterized member of this family, alpha-Conotoxin ImI (alpha-ImI), which is a potent inhibitor of the alpha 7 and alpha 3 beta 2 nAChR subtypes. In this study, we have altered side chains in both the four-residue and the three-residue loops of alpha-RgIA, and have modified its C-terminus. The effects of these changes on activity against alpha 9 alpha 10 and alpha 7 nAChRs were measured; the solution structures of alpha-RgIA and its Y10W, D5E, and P6V analogues were determined from NMR data; and resonance assignments were made for alpha-RgIA [R9A]. The structures for alpha-RglA and its three analogues were well defined, except at the chain termini. Comparison of these structures with reported structures of alpha-ImI reveals a common two-loop backbone architecture within the alpha-4,3 family, but with variations in side-chain solvent accessibility and orientation. Asp5, Pro6, and Arg7 in loop 1 are critical for blockade of both the alpha 9 alpha 10 and the alpha 7 subtypes. In loop 2, alpha-RgIA [Y10W] had activity near that of wild-type alpha-RgIA, with high potency for 000 and low potency for alpha 7, and had a structure similar to that of wild type. By contrast, Arg9 in loop 2 is critical for specific binding to the alpha 9 alpha 10 subtype, probably because it is larger and more solvent accessible than Ala9 in alpha-IMI. Our findings contribute to a better understanding of the molecular basis for antagonism of the alpha 9 alpha 10 nAChR subtype, which is a target for the development of analgesics for the treatment of chronic neuropathic pain. (C) 2008 Elsevier Ltd. All rights reserved.
机译：α-芋螺毒素是锥体蜗牛中的小二硫键约束肽，在特定烟碱型乙酰胆碱受体（nAChRs）亚型中起拮抗剂作用。具有13个残基的肽α-芋螺毒素RgIA（alpha-RgIA）是α-4芋螺毒素的alpha-4,3家族成员，并选择性地阻断alpha 9 alpha 10 nAChR亚型，与此不同，它是另一种公认的成员家族，α-芋螺毒素ImI（α-ImI），是α7和α3beta 2 nAChR亚型的有效抑制剂。在这项研究中，我们改变了alpha-RgIA的四个残基和三个残基环中的侧链，并修饰了其C端。测量了这些变化对针对alpha 9 alpha 10和alpha 7 nAChRs的活性的影响;根据NMR数据确定α-RgIA及其Y10W，D5E和P6V类似物的溶液结构;对α-RgIA[R9A]进行了共振分配。除链末端外，α-RglA及其三个类似物的结构已明确定义。这些结构与已报道的α-ImI结构的比较揭示了α-4,3家族中常见的两环骨架结构，但侧链溶剂可及性和方向有所不同。循环1中的Asp5，Pro6和Arg7对于封锁alpha 9 alpha 10和alpha 7亚型都至关重要。在循环2中，α-RgIA[Y10W]具有接近野生型α-RgIA的活性，对000具有高效力而对α7具有低效力，并且具有与野生型相似的结构。相比之下，环2中的Arg9对于与α9 alpha 10亚型的特异性结合至关重要，可能是因为它比α-IMI中的Ala9更大且溶剂可及性更高。我们的发现有助于更好地理解α9α10 nAChR亚型拮抗作用的分子基础，这是开发用于治疗慢性神经性疼痛的镇痛药的目标。 （C）2008 Elsevier Ltd.保留所有权利。

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