PDBsum entry 2n8h

Toxin

PDB id: 2n8h

Contents

Protein chain

35 a.a.

PDB id:

2n8h

Name:

Toxin

Title:

Structural basis for the inhibition of voltage-gated sodium channels with conotoxin-muoxi-gviij

Structure:

Conotoxin-muoxi-gviij. Chain: a. Engineered: yes

Source:

Synthetic: yes

NMR struc:

20 models

Authors:

B.R.Green,S.Chhabra,R.S.Norton

Key ref:

B.R.Green et al. (2016). Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin μO§-GVIIJ. J Biol Chem, 291, 7205-7220. PubMed id: 26817840 DOI: 10.1074/jbc.M115.697672

Date:

15-Oct-15 Release date: 03-Feb-16

Protein chain

X5IWS1  (O17J_CONGE) -  Mu-conotoxin GVIIJ from Conus geographus

Seq: 82 a.a.

Struc: 35 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1074/jbc.M115.697672

J Biol Chem 291:7205-7220 (2016)

PubMed id: 26817840

Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin μO§-GVIIJ.

B.R.Green, J.Gajewiak, S.Chhabra, J.J.Skalicky, M.M.Zhang, J.E.Rivier, G.Bulaj, B.M.Olivera, D.Yoshikami, R.S.Norton.

ABSTRACT

Cone snail toxins are well known blockers of voltage-gated sodium channels, a property that is of broad interest in biology and therapeutically in treating neuropathic pain and neurological disorders. Although most conotoxin channel blockers function by direct binding to a channel and disrupting its normal ion movement, conotoxin μO§-GVIIJ channel blocking is unique, using both favorable binding interactions with the channel and a direct tether via an intermolecular disulfide bond. Disulfide exchange is possible because conotoxin μO§-GVIIJ contains anS-cysteinylated Cys-24 residue that is capable of exchanging with a free cysteine thiol on the channel surface. Here, we present the solution structure of an analog of μO§-GVIIJ (GVIIJ[C24S]) and the results of structure-activity studies with synthetic μO§-GVIIJ variants. GVIIJ[C24S] adopts an inhibitor cystine knot structure, with two antiparallel β-strands stabilized by three disulfide bridges. The loop region linking the β-strands (loop 4) presents residue 24 in a configuration where it could bind to the proposed free cysteine of the channel (Cys-910, rat NaV1.2 numbering; at site 8). The structure-activity study shows that three residues (Lys-12, Arg-14, and Tyr-16) located in loop 2 and spatially close to residue 24 were also important for functional activity. We propose that the interaction of μO§-GVIIJ with the channel depends on not only disulfide tethering via Cys-24 to a free cysteine at site 8 on the channel but also the participation of key residues of μO§-GVIIJ on a distinct surface of the peptide.