2myz

Publication Abstract from PubMed

Conantokins are ~20 amino acid peptides present in predatory marine snail venoms that function as allosteric antagonists of ion channels of the N-methyl-D-aspartate receptor (NMDAR). These peptides possess a high percentage of post-/co-translationally modified amino acids, particularly gamma-carboxyglutamate (Gla). Appropriately spaced Gla residues allow binding of functional divalent cations, which induces end-to-end alpha-helices in many conantokins. A smaller number of these peptides additionally contain 4-hydroxyproline (HyP). HyP should prevent adoption of the metal ion-induced full alpha-helix, with unknown functional consequences. To address this disparity, as well as the role of HyP in conantokins, we have solved the high-resolution 3D-solution structure of a Gla/HyP-containing 18-residue conantokin, conRl-B, by high-field NMR spectroscopy. We show that HyP10 disrupts only a small region of the alpha-helix of the Mg2+/peptide complex, which displays cation-induced alpha-helices on each terminus of the peptide. The function of conRl-B was examined by measuring its inhibition of NMDA/Gly-mediated current through NMDAR ion channels in mouse cortical neurons. ConRl-B displays high inhibitory selectivity for subclasses of NMDARs that contain the functionally important GluN2B subunit. Replacement of HyP10 with N8Q results in a Mg2+-complexed end-to-end alpha-helix, accompanied by attenuation of NMDAR inhibitory activity. However, replacement of HyP10 with Pro10 allowed the resulting peptide to retain its inhibitory property, but diminished its GluN2B-specificity. Thus, these modified amino acids, in specific peptide backbones, play critical roles in their subunit-selective inhibition of NMDAR ion channels, a finding that can be employed to design NMDAR antagonists that function at ion channels of distinct NMDAR subclasses.

Hydroxyproline-induced Helical Disruption in Conantokin Rl-B Affects Subunit-selective Antagonistic Activities Toward Ion Channels of NMDA Receptors.,Kunda S, Yuan Y, Balsara RD, Zaijcek J, Castellino FJ J Biol Chem. 2015 Jun 5. pii: jbc.M115.650341. PMID:26048991^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.