Construction of cell line heterologously expressing the α6/3β2β3 nicotinic acetylcholine receptor (nAChR) subtype

2011 ◽  
Vol 82 (8) ◽  
pp. 1024-1025
Author(s):  
P. Whiteaker ◽  
L. Lucero ◽  
R.J. Lukas ◽  
C. Hepler ◽  
J.P. Strachan ◽  
...  
Keyword(s):  
Cell Line ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Nachr Subtype

scholarly journals In Silico Finding of Key Interaction Mediated α3β4 and α7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype

2020 ◽  
Vol 21 (17) ◽  
pp. 6189
Author(s):  
Kuntarat Arunrungvichian ◽  
Sumet Chongruchiroj ◽  
Jiradanai Sarasamkan ◽  
Gerrit Schüürmann ◽  
Peter Brust ◽  
...  
Keyword(s):  
Amino Acid ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
In Silico ◽  
Amino Acid Residues ◽  
Nicotinic Acetylcholine ◽  
Selective Binding ◽  
Ligand Selectivity ◽  
Α7 Nachr ◽  
Nachr Subtype

The selective binding of six (S)-quinuclidine-triazoles and their (R)-enantiomers to nicotinic acetylcholine receptor (nAChR) subtypes α3β4 and α7, respectively, were analyzed by in silico docking to provide the insight into the molecular basis for the observed stereospecific subtype discrimination. Homology modeling followed by molecular docking and molecular dynamics (MD) simulations revealed that unique amino acid residues in the complementary subunits of the nAChR subtypes are involved in subtype-specific selectivity profiles. In the complementary β4-subunit of the α3β4 nAChR binding pocket, non-conserved AspB173 through a salt bridge was found to be the key determinant for the α3β4 selectivity of the quinuclidine-triazole chemotype, explaining the 47–327-fold affinity of the (S)-enantiomers as compared to their (R)-enantiomer counterparts. Regarding the α7 nAChR subtype, the amino acids promoting a however significantly lower preference for the (R)-enantiomers were the conserved TyrA93, TrpA149 and TrpB55 residues. The non-conserved amino acid residue in the complementary subunit of nAChR subtypes appeared to play a significant role for the nAChR subtype-selective binding, particularly at the heteropentameric subtype, whereas the conserved amino acid residues in both principal and complementary subunits are essential for ligand potency and efficacy.

scholarly journals Effect of Methionine Oxidation and Substitution of α-Conotoxin TxID on α3β4 Nicotinic Acetylcholine Receptor

Marine Drugs ◽  
2018 ◽  
Vol 16 (6) ◽  
pp. 215 ◽  
Author(s):  
Jie Ren ◽  
Rui Li ◽  
Jiong Ning ◽  
Xiaopeng Zhu ◽  
Dongting Zhangsun ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Methionine Sulfoxide ◽  
Nicotinic Acetylcholine ◽  
Methionine Residue ◽  
Electrophysiological Recordings ◽  
Nachr Subtype ◽  
Potent Inhibition ◽  
Dynamics Simulations ◽  
The Impact

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.

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