Characterization of Conantokin Rl-A: Molecular Phylogeny As Structure/function Study

Overview

Journal J Pept Sci

Specialty Biochemistry

Date 2010 Jun 24

PMID 20572027

Citations 4

Authors

Konkallu H Gowd

Maren Watkins

Vernon D Twede

Grzegorz W Bulaj

Baldomero M Olivera

Affiliations

Soon will be listed here.

Abstract

A multidisciplinary strategy for discovery of new Conus venom peptides combines molecular genetics and phylogenetics with peptide chemistry and neuropharmacology. Here we describe application of this approach to the conantokin family of conopeptides targeting NMDA receptors. A new conantokin from Conus rolani, ConRl-A, was identified using molecular phylogeny and subsequently synthesized and functionally characterized. ConRl-A is a 24-residue peptide containing three gamma-carboxyglutamic acid residues with a number of unique sequence features compared to conantokins previously characterized. The HPLC elution of ConRl-A suggested that this peptide exists as two distinct, slowly exchanging conformers. ConRl-A is predominantly helical (estimated helicity of 50%), both in the presence and absence of Ca(++). The order of potency for blocking the four NMDA receptor subtypes by ConRl-A was NR2B > NR2D > NR2A > NR2C. This peptide has a greater discrimination between NR2B and NR2C than any other ligand reported so far. In summary, ConRl-A is a new member of the conantokin family that expands our understanding of structure/function of this group of peptidic ligands targeted to NMDA receptors. Thus, incorporating phylogeny in the discovery of novel ligands for the given family of ion channels or receptors is an efficient means of exploring the megadiverse group of peptides from the genus Conus.

Citing Articles

Prey-Capture Strategies of Fish-Hunting Cone Snails: Behavior, Neurobiology and Evolution.

Olivera B, Seger J, Horvath M, Fedosov A Brain Behav Evol. 2015; 86(1):58-74.

PMID: 26397110 PMC: 4621268. DOI: 10.1159/000438449.

Hydroxyproline-induced Helical Disruption in Conantokin Rl-B Affects Subunit-selective Antagonistic Activities toward Ion Channels of N-Methyl-d-aspartate Receptors.

Kunda S, Yuan Y, Balsara R, Zajicek J, Castellino F J Biol Chem. 2015; 290(29):18156-18172.

PMID: 26048991 PMC: 4505060. DOI: 10.1074/jbc.M115.650341.

Conantokins derived from the Asprella clade impart conRl-B, an N-methyl d-aspartate receptor antagonist with a unique selectivity profile for NR2B subunits.

Gowd K, Han T, Twede V, Gajewiak J, Smith M, Watkins M Biochemistry. 2012; 51(23):4685-92.

PMID: 22594498 PMC: 4153739. DOI: 10.1021/bi300055n.

Stapling mimics noncovalent interactions of γ-carboxyglutamates in conantokins, peptidic antagonists of N-methyl-D-aspartic acid receptors.

Platt R, Han T, Green B, Smith M, Skalicky J, Gruszczynski P J Biol Chem. 2012; 287(24):20727-36.

PMID: 22518838 PMC: 3370255. DOI: 10.1074/jbc.M112.350462.

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