Structural and Functional Characterization of a Novel α-Conotoxin Mr1.7 from Conus marmoreus Targeting Neuronal nAChR α3β2, α9α10 and α6/α3β2β3 Subtypes

Marine Drugs

Shuo Wang¹  Cong Zhao²  Zhuguo Liu¹  Xuesong Wang²  Na Liu¹  Weihong Du²  Qiuyun Dai¹  Peter Duggan³ 

[1] Beijing Institute of Biotechnology, Beijing 100071, China; E-Mails:;Department of Chemistry, Renmin University of China, Beijing 100872, China; E-Mails:Beijing Institute of Biotechnology, Beijing 100071, China;

关键词: neuronal nicotinic acetylcholine receptor;    α-conotoxin Mr1.7;    Conus marmoreus;    selectivity;    N-terminal sequence;    structure-activity relationship;   

DOI  :  10.3390/md13063259

来源: mdpi

【 摘 要 】

In the present study, we synthesized and, structurally and functionally characterized a novel α4/7-conotoxin Mr1.7 (PECCTHPACHVSHPELC-NH₂), which was previously identified by cDNA libraries from Conus marmoreus in our lab. The NMR solution structure showed that Mr1.7 contained a 3₁₀-helix from residues Pro⁷ to His¹⁰ and a type I β-turn from residues Pro¹⁴ to Cys¹⁷. Electrophysiological results showed that Mr1.7 selectively inhibited the α3β2, α9α10 and α6/α3β2β3 neuronal nicotinic acetylcholine receptors (nAChRs) with an IC₅₀ of 53.1 nM, 185.7 nM and 284.2 nM, respectively, but showed no inhibitory activity on other nAChR subtypes. Further structure-activity studies of Mr1.7 demonstrated that the PE residues at the N-terminal sequence of Mr1.7 were important for modulating its selectivity, and the replacement of Glu² by Ala resulted in a significant increase in potency and selectivity to the α3β2 nAChR. Furthermore, the substitution of Ser¹² with Asn in the loop2 significantly increased the binding of Mr1.7 to α3β2, α3β4, α2β4 and α7 nAChR subtypes. Taken together, this work expanded our knowledge of selectivity and provided a new way to improve the potency and selectivity of inhibitors for nAChR subtypes.

【 授权许可】

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