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PDBsum entry 2ew4
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References listed in PDB file
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Key reference
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Title
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Solution structure of chi-Conopeptide mria, A modulator of the human norepinephrine transporter.
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Authors
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K.P.Nilsson,
E.S.Lovelace,
C.E.Caesar,
N.Tynngård,
P.F.Alewood,
H.M.Johansson,
I.A.Sharpe,
R.J.Lewis,
N.L.Daly,
D.J.Craik.
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Ref.
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Biopolymers, 2005,
80,
815-823.
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PubMed id
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Abstract
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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.
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