Molecular Determinants Conferring the Stoichiometric-Dependent Activity of α-Conotoxins at the Human α9α10 Nicotinic Acetylcholine Receptor Subtype

J Med Chem. 2018 May 24;61(10):4628-4634. doi: 10.1021/acs.jmedchem.8b00115. Epub 2018 May 15.

Abstract

α9α10 nicotinic acetylcholine receptors (nAChRs) putatively exist at different stoichiometries. We systematically investigated the molecular determinants of α-conotoxins Vc1.1, RgIA#, and PeIA inhibition at hypothetical stoichiometries of the human α9α10 nAChR. Our results suggest that only Vc1.1 exhibits stoichiometric-dependent inhibition at the α9α10 nAChR. The hydrogen bond between N154 of α9 and D11 of Vc1.1 at the α9(+)-α9(-) interface is responsible for the stoichiometric-dependent potency of Vc1.1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Conotoxins / chemistry*
  • Conotoxins / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Nicotinic Antagonists / chemistry
  • Nicotinic Antagonists / pharmacology
  • Oocytes / cytology
  • Oocytes / drug effects*
  • Oocytes / metabolism
  • Protein Conformation
  • Protein Subunits
  • Receptors, Nicotinic / chemistry*
  • Receptors, Nicotinic / classification
  • Receptors, Nicotinic / metabolism*
  • Xenopus laevis

Substances

  • Conotoxins
  • Nicotinic Antagonists
  • Protein Subunits
  • Receptors, Nicotinic
  • alpha-conotoxin Vc1.1