Different residues in channel turret determining the selectivity of ADWX-1 inhibitor peptide between Kv1.1 and Kv1.3 channels

J Proteome Res. 2008 Nov;7(11):4890-7. doi: 10.1021/pr800494a. Epub 2008 Oct 21.

Abstract

The low selectivity of Kv1 peptide inhibitors for specific isoforms makes them poor candidates for the development of theraputics. Using combined approaches, we showed that the Kv1 turret is the critical determinant for ADWX-1 peptide inhibitor selectivity of Kv1.3 over Kv1.1. Mutation of Kv1.1 turret residues to match the sequence of Kv1.3 lead to increased inhibition of Kv1.1 activity. These studies may lead to improvements in peptide inhibitor drug development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / chemistry*
  • Animals
  • Computer Simulation
  • Disulfides / chemistry
  • Dose-Response Relationship, Drug
  • Hydrogen Bonding
  • Kv1.1 Potassium Channel / antagonists & inhibitors*
  • Kv1.1 Potassium Channel / chemistry
  • Kv1.1 Potassium Channel / genetics
  • Kv1.3 Potassium Channel / antagonists & inhibitors*
  • Kv1.3 Potassium Channel / chemistry
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Nuclear Magnetic Resonance, Biomolecular
  • Oligopeptides / pharmacology*
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacology*
  • Protein Conformation
  • Protein Structure, Secondary
  • Sensitivity and Specificity
  • Sequence Homology, Amino Acid

Substances

  • Amino Acids
  • Disulfides
  • Kv1.3 Potassium Channel
  • Oligopeptides
  • Potassium Channel Blockers
  • Kv1.1 Potassium Channel