8FLP

NMR Solution Structure of LvIC analogue

Summary for 8FLP

• Entry DOI: 10.2210/pdb8flp/pdb
• NMR Information: BMRB: 31066
• Descriptor: Alpha-conotoxin LvIC analogue (1 entity in total)
• Functional Keywords: nachrs, toxin
• Biological source: Conus lividus
• Total number of polymer chains: 1
• Total formula weight: 1305.55

Authors

Harvey, P.J.,Craik, D.J. (deposition date: 2022-12-22, release date: 2023-02-08, Last modification date: 2024-11-06)

Primary citation

Zhu, X.,Wang, S.,Kaas, Q.,Yu, J.,Wu, Y.,Harvey, P.J.,Zhangsun, D.,Craik, D.J.,Luo, S.
Discovery, Characterization, and Engineering of LvIC, an alpha 4/4-Conotoxin That Selectively Blocks Rat alpha 6/ alpha 3 beta 4 Nicotinic Acetylcholine Receptors.
J.Med.Chem., 66:2020-2031, 2023

PubMed Abstract: α6β4 nicotinic acetylcholine receptors (nAChRs) are expressed in the central and peripheral nervous systems, but their functions are not fully understood, largely because of a lack of specific ligands. Here, we characterized a novel α-conotoxin, LvIC, and designed a series of analogues to probe structure-activity relationships at the α6β4 nAChR. The potency and selectivity of these conotoxins were tested using two-electrode voltage-clamp recording on nAChR subtypes expressed in oocytes. One of the analogues, [D1G,ΔQ14]LvIC, potently blocked α6/α3β4 nAChRs (α6/α3 is a chimera) with an IC of 19 nM, with minimal activity at other nAChR subtypes, including the structurally similar α6/α3β2β3 and α3β4 subtypes. Using NMR, molecular docking, and receptor mutation, structure-activity relationships of [D1G,ΔQ14]LvIC at the α6/α3β4 nAChR were defined. It is a potent and specific antagonist of α6β4 nAChRs that could potentially serve as a novel molecular probe to explore α6β4 nAChR-related neurophysiological and pharmacological functions.

PubMed: 36682014
DOI: 10.1021/acs.jmedchem.2c01786

Experimental method

SOLUTION NMR