PDBsum entry 2ew4

Toxin

PDB id: 2ew4

Contents

Protein chain

14 a.a.

PDB id:

2ew4

Name:

Toxin

Title:

Solution structure of mria

Structure:

Mria. Chain: a. Engineered: yes

Source:

Synthetic: yes. Conus marmoreus. Organism_taxid: 42752

NMR struc:

20 models

Authors:

K.P.Nilsson,E.S.Lovelace,C.E.Caesar,N.Tynngard,P.F.Alewood, H.M.Johansson,I.A.Sharpe,R.J.Lewis,N.L.Daly,D.J.Craik

Key ref:

K.P.Nilsson et al. (2005). Solution structure of chi-conopeptide MrIA, a modulator of the human norepinephrine transporter. Biopolymers, 80, 815-823. PubMed id: 15931669

Date:

02-Nov-05 Release date: 15-Nov-05

Protein chain

P58808  (CTA1A_CONMR) -  Chi-conotoxin MrIA from Conus marmoreus

Seq: 61 a.a.

Struc: 14 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Biopolymers 80:815-823 (2005)

PubMed id: 15931669

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

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.

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.