2LU6: NMR solution structure of Midi peptide designed based on m-conotoxins

Citation:
Abstract
To date, cone snail toxins ("conotoxins") are of great interest in the pursuit of novel subtype-selective modulators of voltage-gated sodium channels (Na(v)s). Na(v)s participate in a wide range of electrophysiological processes. Consequently, their malfunctioning has been associated with numerous diseases. The development of subtype-selective modulators of Na(v)s remains highly important in the treatment of such disorders. In current research, a series of novel, synthetic, and bioactive compounds were designed based on two naturally occurring mu-conotoxins that target Na(v)s. The initial designed peptide contains solely 13 amino acids and was therefore named "Mini peptide." It was derived from the mu-conotoxins KIIIA and BuIIIC. Based on this Mini peptide, 10 analogues were subsequently developed, comprising 12-16 amino acids with two disulfide bridges. Following appropriate folding and mass verification, blocking effects on Na(v)s were investigated. The most promising compound established an IC(50) of 34.1 +/- 0.01 nM (R2-Midi on Na(v)1.2). An NMR structure of one of our most promising compounds was determined. Surprisingly, this structure does not reveal an alpha-helix. We prove that it is possible to design small peptides based on known pharmacophores of mu-conotoxins without losing their potency and selectivity. These data can provide crucial material for further development of conotoxin-based therapeutics.
PDB ID: 2LU6Download
MMDB ID: 100805
PDB Deposition Date: 2012/6/8
Updated in MMDB: 2013/08
Experimental Method:
solution nmr
Similar Structures:
Biological Unit for 2LU6: monomeric; determined by author
Molecular Components in 2LU6
Label Count Molecule
Protein (1 molecule)
1
Midi Peptide Designed Based on M-conotoxins
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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