6CGX

Backbone cyclised conotoxin Vc1.1 mutant - D11A, E14A

6CGX の概要

• エントリーDOI: 10.2210/pdb6cgx/pdb
• NMR情報: BMRB: 30412
• 分子名称: Alpha-conotoxin Vc1A (1 entity in total)
• 機能のキーワード: structure from molmol, toxin
• 由来する生物種: Conus victoriae (Queen Victoria cone)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 2082.33

構造登録者

Clark, R.J. (登録日: 2018-02-21, 公開日: 2018-05-23, 最終更新日: 2024-11-06)

主引用文献

Sadeghi, M.,Carstens, B.B.,Callaghan, B.P.,Daniel, J.T.,Tae, H.S.,O'Donnell, T.,Castro, J.,Brierley, S.M.,Adams, D.J.,Craik, D.J.,Clark, R.J.
Structure-Activity Studies Reveal the Molecular Basis for GABAB-Receptor Mediated Inhibition of High Voltage-Activated Calcium Channels by alpha-Conotoxin Vc1.1.
ACS Chem. Biol., 13:1577-1587, 2018

PubMed Abstract: α-Conotoxins are disulfide-bonded peptides from cone snail venoms and are characterized by their affinity for nicotinic acetylcholine receptors (nAChR). Several α-conotoxins with distinct selectivity for nAChR subtypes have been identified as potent analgesics in animal models of chronic pain. However, a number of α-conotoxins have been shown to inhibit N-type calcium channel currents in rodent dissociated dorsal root ganglion (DRG) neurons via activation of G protein-coupled GABA receptors (GABAR). Therefore, it is unclear whether activation of GABAR or inhibition of α9α10 nAChRs is the analgesic mechanism. To investigate the mechanisms by which α-conotoxins provide analgesia, we synthesized a suite of Vc1.1 analogues where all residues, except the conserved cysteines, in Vc1.1 were individually replaced by alanine (A), lysine (K), and aspartic acid (D). Our results show that the amino acids in the first loop play an important role in binding of the peptide to the receptor, whereas those in the second loop play an important role for the selectivity of the peptide for the GABAR over α9α10 nAChRs. We designed a cVc1.1 analogue that is >8000-fold selective for GABAR-mediated inhibition of high voltage-activated (HVA) calcium channels over α9α10 nAChRs and show that it is analgesic in a mouse model of chronic visceral hypersensitivity (CVH). cVc1.1[D11A,E14A] caused dose-dependent inhibition of colonic nociceptors with greater efficacy in ex vivo CVH colonic nociceptors relative to healthy colonic nociceptors. These findings suggest that selectively targeting GABAR-mediated HVA calcium channel inhibition by α-conotoxins could be effective for the treatment of chronic visceral pain.

PubMed: 29746088
DOI: 10.1021/acschembio.8b00190

実験手法

SOLUTION NMR