Solution structure of χ-conopeptide MrIA, a modulator of the human norepinephrine transporter

Nilsson, K. P. R., Lovelace, E. S., Caesar, C. E., Tynngard, N., Alewood, P. F., Johansson, H. M., Sharpe, I. A., Lewis, R. J., Daly, N. L. and Craik, D. J. (2005) Solution structure of χ-conopeptide MrIA, a modulator of the human norepinephrine transporter. Biopolymers, 80 6: 815-823. doi:10.1002/bip.20302


Author Nilsson, K. P. R.
Lovelace, E. S.
Caesar, C. E.
Tynngard, N.
Alewood, P. F.
Johansson, H. M.
Sharpe, I. A.
Lewis, R. J.
Daly, N. L.
Craik, D. J.
Title Solution structure of χ-conopeptide MrIA, a modulator of the human norepinephrine transporter
Journal name Biopolymers   Check publisher's open access policy
ISSN 0006-3525
Publication date 2005
Sub-type Article (original research)
DOI 10.1002/bip.20302
Volume 80
Issue 6
Start page 815
End page 823
Total pages 9
Place of publication Hoboken
Publisher John Wiley & Sons Inc
Language eng
Subject C1
250203 Solid State Chemistry
780103 Chemical sciences
Abstract The chi-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 hairpin with the two strands connected by an inverse gamma-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. L; Kaye, D. M.; Adams, D. I.; Alewood, P. F.; Lewis, R. J. J Biol Client 2003, 278, 40317-40323), which appears to be more flexible than the beta-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 Hypl2 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 chi-conopeptide potency. 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 entailing the Biopolymers editorial office at biopolymers@wiley.com (c) 2005 Wiley Periodicals, Inc.
Keyword Biochemistry & Molecular Biology
Biophysics
Contoxin
Norepinephrine Transporter
Peptide Synthesis
Structure
Nmr
3-dimensional Solution Structure
Alpha-conotoxin
Nmr-spectroscopy
Conus-marmoreus
Sodium-channels
Peptides
Proteins
Venom
Noradrenaline
Inhibition
Q-Index Code C1

 
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Created: Mon, 13 Aug 2007, 15:45:22 EST