2MG6

Non-reducible analogues of alpha-conotoxin Vc1.1: [3,16]-trans dicarba Vc1.1

Summary for 2MG6

• Entry DOI: 10.2210/pdb2mg6/pdb
• Related: 2MFX 2MFY
• NMR Information: BMRB: 19587
• Descriptor: Alpha-conotoxin Vc1A (1 entity in total)
• Functional Keywords: dicarba, toxin
• Biological source: Conus victoriae (Queen Victoria cone snail)
• Total number of polymer chains: 1
• Total formula weight: 1775.94

Authors

Robinson, S.D.,Macraild, C.A.,Van Lierop, B.J.,Robinson, A.J.,Norton, R.S. (deposition date: 2013-10-28, release date: 2013-12-18)

Primary citation

van Lierop, B.J.,Robinson, S.D.,Kompella, S.N.,Belgi, A.,McArthur, J.R.,Hung, A.,MacRaild, C.A.,Adams, D.J.,Norton, R.S.,Robinson, A.J.
Dicarba alpha-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors.
Acs Chem.Biol., 8:1815-1821, 2013

PubMed Abstract: Conotoxins have emerged as useful leads for the development of novel therapeutic analgesics. These peptides, isolated from marine molluscs of the genus Conus, have evolved exquisite selectivity for receptors and ion channels of excitable tissue. One such peptide, α-conotoxin Vc1.1, is a 16-mer possessing an interlocked disulfide framework. Despite its emergence as a potent analgesic lead, the molecular target and mechanism of action of Vc1.1 have not been elucidated to date. In this paper we describe the regioselective synthesis of dicarba analogues of Vc1.1 using olefin metathesis. The ability of these peptides to inhibit acetylcholine-evoked current at rat α9α10 and α3β4 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes has been assessed in addition to their ability to inhibit high voltage-activated (HVA) calcium channel current in isolated rat DRG neurons. Their solution structures were determined by NMR spectroscopy. Significantly, we have found that regioselective replacement of the native cystine framework with a dicarba bridge can be used to selectively tune the cyclic peptide's innate biological activity for one receptor over another. The 2,8-dicarba Vc1.1 isomer retains activity at γ-aminobutyric acid (GABAB) G protein-coupled receptors, whereas the isomeric 3,16-dicarba Vc1.1 peptide retains activity at the α9α10 nAChR subtype. These singularly acting analogues will enable the elucidation of the biological target responsible for the peptide's potent analgesic activity.

PubMed: 23768016
DOI: 10.1021/cb4002393

Experimental method

SOLUTION NMR