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Marine Drugs, Vol. 16, Pages 215: Effect of Methionine Oxidation and Substitution of α-Conotoxin TxID on α3β4 Nicotinic Acetylcholine Receptor

Marine Drugs, Vol. 16, Pages 215: Effect of Methionine Oxidation and Substitution of α-Conotoxin TxID on α3β4 Nicotinic Acetylcholine Receptor

Marine Drugs doi: 10.3390/md16060215

Authors: Jie Ren Rui Li Jiong Ning Xiaopeng Zhu Dongting Zhangsun Yong Wu Sulan Luo

α-Conotoxin TxID was discovered from Conus textile by gene cloning, which has 4/6 inter-cysteine loop spacing and selectively inhibits α3β4 nicotinic acetylcholine receptor (nAChR) subtype. However, TxID is susceptible to modification due to it containing a methionine (Met) residue that easily forms methionine sulfoxide (MetO) in oxidative environment. In this study, we investigated how Met-11 and its derivatives affect the activity of TxID using a combination of electrophysiological recordings and molecular modelling. The results showed most TxID analogues had substantially decreased activities on α3β4 nAChR with more than 10-fold potency loss and 5 of them demonstrated no inhibition on α3β4 nAChR. However, one mutant, [M11I]TxID, displayed potent inhibition at α3β4 nAChR with an IC50 of 69 nM, which only exhibited 3.8-fold less compared with TxID. Molecular dynamics simulations were performed to expound the decrease in the affinity for α3β4 nAChR. The results indicate replacement of Met with a hydrophobic moderate-sized Ile in TxID is an alternative strategy to reduce the impact of Met oxidation, which may help to redesign conotoxins containing methionine residue.

Authors:   Ren, Jie ; Li, Rui ; Ning, Jiong ; Zhu, Xiaopeng ; Zhangsun, Dongting ; Wu, Yong ; Luo, Sulan
Journal:   Marine Drugs
Volume:   16
edition:   6
Year:   2018
Pages:   215
DOI:   10.3390/md16060215
Publication date:   20-Jun-2018
Facts, background information, dossiers
  • Substitution
  • Replacement
  • Oxidation
More about Molecular Diversity Preservation International
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