HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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 beta-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. 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 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 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 chi-conopeptide potency.
AuthorsK Peter R Nilsson, Erica S Lovelace, Christina E Caesar, Nahreen Tynngård, Paul F Alewood, Helena M Johansson, Iain A Sharpe, Richard J Lewis, Norelle L Daly, David J Craik
JournalBiopolymers (Biopolymers) Vol. 80 Issue 6 Pg. 815-23 ( 2005) ISSN: 0006-3525 [Print] United States
PMID15931669 (Publication Type: Journal Article)
CopyrightCopyright 2005 Wiley Periodicals, Inc.
Chemical References
  • Conotoxins
  • Disulfides
  • Mollusk Venoms
  • Peptides
  • Solutions
  • Symporters
  • chi-conopeptide MrIA, Conus
  • Water
  • Alanine
  • Norepinephrine
Topics
  • Alanine (metabolism)
  • Amino Acid Substitution
  • Animals
  • Chromatography, High Pressure Liquid
  • Computer Simulation
  • Conotoxins (chemistry, metabolism, pharmacology)
  • Conus Snail
  • Disulfides (chemistry)
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Epididymis (anatomy & histology, surgery)
  • Humans
  • Hydrogen-Ion Concentration
  • Male
  • Molecular Conformation
  • Mollusk Venoms (chemistry, classification, pharmacology)
  • Norepinephrine (metabolism)
  • Nuclear Magnetic Resonance, Biomolecular
  • Oxidation-Reduction
  • Peptides (chemical synthesis, chemistry, classification, genetics, isolation & purification, metabolism, pharmacology)
  • Protein Binding
  • Rats
  • Solutions
  • Spectrum Analysis, Raman
  • Stereoisomerism
  • Symporters (metabolism)
  • Vas Deferens (drug effects, physiology)
  • Water (chemistry)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: