2n8h

Publication Abstract from PubMed

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 muO section sign-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 muO section sign-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 muO section sign-GVIIJ (GVIIJ[C24S]) and the results of structure-activity studies with synthetic muO section sign-GVIIJ variants. GVIIJ[C24S] adopts an inhibitor cystine knot structure, with two antiparallel beta-strands stabilized by three disulfide bridges. The loop region linking the beta-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 muO section sign-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 muO section sign-GVIIJ on a distinct surface of the peptide.

Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin muO section sign-GVIIJ.,Green BR, Gajewiak J, Chhabra S, Skalicky JJ, Zhang MM, Rivier JE, Bulaj G, Olivera BM, Yoshikami D, Norton RS J Biol Chem. 2016 Mar 25;291(13):7205-20. doi: 10.1074/jbc.M115.697672. Epub 2016, Jan 27. PMID:26817840^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.