Structure-activity relationships of omega-conotoxins MVIIA, MVIIC and 14 loop splice hybrids at N and P/Q-type calcium channels

J Mol Biol. 1999 Jun 25;289(5):1405-21. doi: 10.1006/jmbi.1999.2817.


The omega-conotoxins are a set of structurally related, four-loop, six cysteine containing peptides, that have a range of selectivities for different subtypes of the voltage-sensitive calcium channel (VSCC). To investigate the basis of the selectivity displayed by these peptides, we have studied the binding affinities of two naturally occurring omega-conotoxins, MVIIA and MVIIC and a series of 14 MVIIA/MVIIC loop hybrids using radioligand binding assays for N and P/Q-type Ca2+channels in rat brain tissue. A selectivity profile was developed from the ratio of relative potencies at N-type VSCCs (using [125I]GVIA radioligand binding assays) and P/Q-type VSCCs (using [125I]MVIIC radioligand binding assays). In these peptides, loops 2 and 4 make the greatest contribution to VSCC subtype selectivity, while the effects of loops 1 and 3 are negligible. Peptides with homogenous combinations of loop 2 and 4 display clear selectivity preferences, while those with heterogeneous combinations of loops 2 and 4 are less discriminatory. 1H NMR spectroscopy revealed that the global folds of MVIIA, MVIIC and the 14 loop hybrid peptides were similar; however, several differences in local structure were identified. Based on the binding data and the 3D structures of MVIIA, GVIA and MVIIC, we have developed a preliminary pharmacophore based on the omega-conotoxin residues most likely to interact with the N-type VSCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium Channel Blockers / chemistry*
  • Calcium Channel Blockers / metabolism
  • Calcium Channels / chemistry*
  • Calcium Channels / metabolism
  • Molecular Sequence Data
  • Mollusk Venoms / chemistry*
  • Mollusk Venoms / metabolism
  • Peptides / chemistry*
  • Peptides / metabolism
  • Protein Conformation
  • RNA Splicing*
  • Rats
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship
  • omega-Conotoxins*


  • Calcium Channel Blockers
  • Calcium Channels
  • Mollusk Venoms
  • Peptides
  • omega-Conotoxins
  • omega-conotoxin-MVIIC
  • ziconotide