2N8H
Structural basis for the inhibition of voltage-gated sodium channels with conotoxin-muOxi-GVIIJ
Summary for 2N8H
| Entry DOI | 10.2210/pdb2n8h/pdb |
| NMR Information | BMRB: 26674 |
| Descriptor | conotoxin-muOxi-GVIIJ (1 entity in total) |
| Functional Keywords | inhibitor cysteine knot, toxin |
| Total number of polymer chains | 1 |
| Total formula weight | 3734.25 |
| Authors | Green, B.R.,Chhabra, S.,Norton, R.S. (deposition date: 2015-10-15, release date: 2016-02-03, Last modification date: 2023-06-14) |
| Primary citation | Green, B.R.,Gajewiak, J.,Chhabra, S.,Skalicky, J.J.,Zhang, M.M.,Rivier, J.E.,Bulaj, G.,Olivera, B.M.,Yoshikami, D.,Norton, R.S. Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin mu O-GVIIJ. J.Biol.Chem., 291:7205-7220, 2016 Cited by PubMed 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. PubMed: 26817840DOI: 10.1074/jbc.M115.697672 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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