2MDQ

A Novel 4/7-Conotoxin LvIA from Conus lividus that Selectively Blocks 3 2 vs. 6/3 2 3 Nicotinic Acetylcholine Receptors

Summary for 2MDQ

• Entry DOI: 10.2210/pdb2mdq/pdb
• NMR Information: BMRB: 19501
• Descriptor: Alpha-conotoxin-like (1 entity in total)
• Functional Keywords: conotoxin, disulfide rich, toxin, alfa-conotoxins, nicotinic acetylcholine receptor
• Biological source: Conus lividus (Livid cone)
• Cellular location: Secreted (By similarity): L8BU87
• Total number of polymer chains: 1
• Total formula weight: 1684.92

Authors

Schroeder, C.I. (deposition date: 2013-09-16, release date: 2014-02-12, Last modification date: 2024-10-16)

Primary citation

Luo, S.,Zhangsun, D.,Schroeder, C.I.,Zhu, X.,Hu, Y.,Wu, Y.,Weltzin, M.M.,Eberhard, S.,Kaas, Q.,Craik, D.J.,McIntosh, J.M.,Whiteaker, P.
A novel alpha 4/7-conotoxin LvIA from Conus lividus that selectively blocks alpha 3 beta 2 vs. alpha 6/ alpha 3 beta 2 beta 3 nicotinic acetylcholine receptors.
Faseb J., 28:1842-1853, 2014

PubMed Abstract: This study was performed to discover and characterize the first potent α3β2-subtype-selective nicotinic acetylcholine receptor (nAChR) ligand. A novel α4/7-conotoxin, α-CTxLvIA, was cloned from Conus lividus. Its pharmacological profile at Xenopus laevis oocyte-expressed rat nAChR subtypes was determined by 2-electrode voltage-clamp electrophysiology, and its 3-dimensional (3D) structure was determined by NMR spectroscopy. α-CTx LvIA is a 16-aa C-terminally-amidated peptide with 2-disulfide bridges. Using rat subunits expressed in Xenopus oocytes, we found the highest affinity of α-CTxLvIA was for α3β2 nAChRs (IC50 8.7 nM), where blockade was reversible within 2 min. IC50 values were >100 nM at α6/α3β2β3, α6/α3β4, and α3β4 nAChRs, and ≥3 μM at all other subtypes tested. α3β2 vs. α6β2 subtype selectivity was confirmed for human-subunit nAChRs with much greater preference (300-fold) for α3β2 over α6β2 nAChRs. This is the first α-CTx reported to show high selectivity for human α3β2 vs. α6β2 nAChRs. α-CTxLvIA adopts two similarly populated conformations water: one (assumed to be bioactive) is highly structured, whereas the other is mostly random coil in nature. Selectivity differences with the similarly potent, but less selective, α3β2 nAChR antagonist α-CTx PeIA probably reside within the three residues, which differ in loop 2, given their otherwise similar 3D structures. α4/7-CTx LvIA is a new, potent, selective α3β2 nAChR antagonist, which will enable detailed studies of α3β2 nAChR structure, function, and physiological roles.

PubMed: 24398291
DOI: 10.1096/fj.13-244103

Experimental method

SOLUTION NMR