scholarly journals Generation of Candidate Ligands for Nicotinic Acetylcholine Receptors via in situ Click Chemistry with a Soluble Acetylcholine Binding Protein Template

2012 ◽  
Vol 134 (15) ◽  
pp. 6732-6740 ◽  
Author(s):  
Neil P. Grimster ◽  
Bernhard Stump ◽  
Joseph R. Fotsing ◽  
Timo Weide ◽  
Todd T. Talley ◽  
...  
Keyword(s):  
Click Chemistry ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Binding Protein ◽  
Nicotinic Acetylcholine ◽  
Acetylcholine Binding Protein

scholarly journals Ligand design for human nicotinic acetylcholine receptors using in situ freeze‐frame click chemistry

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
John Yamauchi ◽  
Akos Nemecz ◽  
Kwok‐Yiu Ho ◽  
Joseph R. Fotsing ◽  
Timo Weide ◽  
...  
Keyword(s):  
Click Chemistry ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Ligand Design ◽  
Nicotinic Acetylcholine

scholarly journals Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thao N. T. Ho ◽  
Nikita Abraham ◽  
Richard J. Lewis
Keyword(s):  
Crystal Structures ◽  
Nicotinic Acetylcholine Receptors ◽  
Molecular Basis ◽  
Disulfide Bonds ◽  
Acetylcholine Receptors ◽  
Binding Protein ◽  
Wild Type ◽  
Critical Determinant ◽  
Nicotinic Acetylcholine ◽  
Acetylcholine Binding Protein

Abstractα-Conotoxins are small disulfide-rich peptides targeting nicotinic acetylcholine receptors (nAChRs) characterised by a CICII-Xm-CIII-Xn-CIV framework that invariably adopt the native globular conformations which is typically most potent. α-Conotoxins are divided into several structural subgroups based on the number of residues within the two loops braced by the disulfide bonds (m/n), with the 4/7 and 4/3 subgroups dominating. AusIA is a relatively rare α5/5-conotoxin isolated from the venom of Conus australis. Surprisingly, the ribbon isomer displayed equipotency to the wild-type globular AusIA at human α7-containing nAChR. To understand the molecular basis for equipotency, we determined the co-crystal structures of both isomers at Lymnea stagnalis acetylcholine binding protein. The additional residue in the first loop of AusIA was found to be a critical determinant of equipotency, with 11-fold and 86-fold shifts in potency in favour of globular AusIA over ribbon AusIA observed following deletion of Ala4 or Arg5, respectively. This divergence in the potency between globular AusIA and ribbon AusIA was further enhanced upon truncation of the non-conserved Val at the C-termini. Conversely, equipotency could be replicated in LsIA and TxIA [A10L] following insertion of an Ala in the first loop. These findings provide a new understanding of the role the first loop in ribbon and globular α-conotoxins can play in directing α-conotoxin nAChR pharmacology.

Sign in / Sign up

Export Citation Format

Share Document