2005/01/01 by K. Peter R. Nilsson, Erica S. Lovelace, Christina E.B. Caesar +9 · 6 citations
Biochemistry, Genetics and Molecular Biology · #Biochemical and Structural Characterization #Chemical Synthesis and Analysis #Nicotinic Acetylcholine Receptors Study
paper · doi:10.1002/bip.20302
Abstract The χ ‐conopeptides MrIA and MrIB are 13‐residue peptides with two disulfide bonds that inhibit human and rat norepinephrine transporter systems and are of significant interest for the design of novel drugs involved in pain treatment. In the current study we have determined the solution structure of MrIA using NMR spectroscopy. The major element of secondary structure is a β ‐hairpin with the two strands connected by an inverse γ‐turn. The residues primarily involved in activity have previously been shown to be located in the turn region (Sharpe, I. A.; Palant, E.; Schroder, C. I.; Kaye, D. M.; Adams, D. J.; Alewood, P. F.; Lewis, R. J. J Biol Chem 2003, 278, 40317–40323), which appears to be more flexible than the β ‐strands based on disorder in the ensemble of calculated structures. Analogues of MrIA with N‐terminal truncations indicate that the N‐terminal residues play a role in defining a stable conformation and the native disulfide connectivity. In particular, noncovalent interactions between Val3 and Hyp12 are likely to be involved in maintaining a stable conformation. The N‐terminus also affects activity, as a single N‐terminal deletion introduced additional pharmacology at rat vas deferens, while deleting the first two amino acids reduced χ‐conopeptide potency. © 2005 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 80: 815–823, 2005 This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at [email protected]