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Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin µO§-GVIIJ.
Green, Brad R; Gajewiak, Joanna; Chhabra, Sandeep; Skalicky, Jack J; Zhang, Min-Min; Rivier, Jean E; Bulaj, Grzegorz; Olivera, Baldomero M; Yoshikami, Doju; Norton, Raymond S.
Afiliación
  • Green BR; From the Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia, the Department of Biology, University of Utah, Salt Lake City, Utah 84112.
  • Gajewiak J; the Department of Biology, University of Utah, Salt Lake City, Utah 84112.
  • Chhabra S; From the Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • Skalicky JJ; the Department of Biochemistry and.
  • Zhang MM; the Department of Biology, University of Utah, Salt Lake City, Utah 84112.
  • Rivier JE; the Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037.
  • Bulaj G; the Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah 84108, and.
  • Olivera BM; the Department of Biology, University of Utah, Salt Lake City, Utah 84112.
  • Yoshikami D; the Department of Biology, University of Utah, Salt Lake City, Utah 84112, yoshikami@bioscience.utah.edu.
  • Norton RS; From the Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia, ray.norton@monash.edu.
J Biol Chem ; 291(13): 7205-20, 2016 Mar 25.
Article en En | MEDLINE | ID: mdl-26817840
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 ß-strands stabilized by three disulfide bridges. The loop region linking the ß-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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Canales de Sodio / Conotoxinas / Bloqueadores de los Canales de Sodio / Disulfuros / Canal de Sodio Activado por Voltaje NAV1.2 / Proteínas Musculares Límite: Animals Idioma: En Revista: J Biol Chem Año: 2016 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Canales de Sodio / Conotoxinas / Bloqueadores de los Canales de Sodio / Disulfuros / Canal de Sodio Activado por Voltaje NAV1.2 / Proteínas Musculares Límite: Animals Idioma: En Revista: J Biol Chem Año: 2016 Tipo del documento: Article