Residues Responsible for the Selectivity of α-Conotoxins for Ac-AChBP or nAChRs

Mar Drugs. 2016 Oct 11;14(10):173. doi: 10.3390/md14100173.

Abstract

Nicotinic acetylcholine receptors (nAChRs) are targets for developing new drugs to treat severe pain, nicotine addiction, Alzheimer disease, epilepsy, etc. α-Conotoxins are biologically and chemically diverse. With 12-19 residues and two disulfides, they can be specifically selected for different nAChRs. Acetylcholine-binding proteins from Aplysia californica (Ac-AChBP) are homologous to the ligand-binding domains of nAChRs and pharmacologically similar. X-ray structures of the α-conotoxin in complex with Ac-AChBP in addition to computer modeling have helped to determine the binding site of the important residues of α-conotoxin and its affinity for nAChR subtypes. Here, we present the various α-conotoxin residues that are selective for Ac-AChBP or nAChRs by comparing the structures of α-conotoxins in complex with Ac-AChBP and by modeling α-conotoxins in complex with nAChRs. The knowledge of these binding sites will assist in the discovery and design of more potent and selective α-conotoxins as drug leads.

Keywords: Ac-AChBP; X-ray structure; design; model; nAChRs; α-conotoxins.

Publication types

  • Review

MeSH terms

  • Acetylcholine / metabolism*
  • Animals
  • Aplysia
  • Conotoxins / metabolism*
  • Crystallography, X-Ray
  • Oceans and Seas
  • Protein Binding
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / metabolism*

Substances

  • Conotoxins
  • Receptors, Nicotinic
  • Acetylcholine