Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Structure and sodium channel activity of an excitatory I1-superfamily conotoxin.
Buczek O
,
Wei D
,
Babon JJ
,
Yang X
,
Fiedler B
,
Chen P
,
Yoshikami D
,
Olivera BM
,
Bulaj G
,
Norton RS
.
Abstract
Conotoxin iota-RXIA, from the fish-hunting species Conus radiatus, is a member of the recently characterized I1-superfamily, which contains eight cysteine residues arranged in a -C-C-CC-CC-C-C- pattern. iota-RXIA (formerly designated r11a) is one of three characterized I1 peptides in which the third last residue is posttranslationally isomerized to the d configuration. Naturally occurring iota-RXIA with d-Phe44 is significantly more active as an excitotoxin than the l-Phe analogue both in vitro and in vivo. We have determined the solution structures of both forms by NMR spectroscopy, the first for an I1-superfamily member. The disulfide connectivities were determined from structure calculations and confirmed chemically as 5-19, 12-22, 18-27, and 21-38, suggesting that iota-RXIA has an ICK structural motif with one additional disulfide (21-38). Indeed, apart from the first few residues, the structure is well defined up to around residue 35 and does adopt an ICK structure. The C-terminal region, including Phe44, is disordered. Comparison of the d-Phe44 and l-Phe44 forms indicates that the switch from one enantiomer to the other has very little effect on the structure, even though it is clearly important for receptor interaction based on activity data. Finally, we identify the target of iota-RXIA as a voltage-gated sodium channel; iota-RXIA is an agonist, shifting the voltage dependence of activation of mouse NaV1.6 expressed in Xenopus oocytes to more hyperpolarized potentials. Thus, there is a convergence of structure and function in iota-RXIA, as its disulfide pairing and structure resemble those of funnel web spider toxins that also target sodium channels.
Adams,
Structure and properties of omega-agatoxin IVB, a new antagonist of P-type calcium channels.
1993, Pubmed
Adams,
Structure and properties of omega-agatoxin IVB, a new antagonist of P-type calcium channels.
1993,
Pubmed
Bartels,
The program XEASY for computer-supported NMR spectral analysis of biological macromolecules.
1995,
Pubmed
Berman,
The Protein Data Bank.
2000,
Pubmed
Buczek,
Post-translational amino acid isomerization: a functionally important D-amino acid in an excitatory peptide.
2005,
Pubmed
Buczek,
Conotoxins and the posttranslational modification of secreted gene products.
2005,
Pubmed
Buczek,
Characterization of D-amino-acid-containing excitatory conotoxins and redefinition of the I-conotoxin superfamily.
2005,
Pubmed
Caldwell,
Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses.
2000,
Pubmed
Corzo,
Solution structure and alanine scan of a spider toxin that affects the activation of mammalian voltage-gated sodium channels.
2007,
Pubmed
,
Xenbase
Dingley,
Measuring protein self-association using pulsed-field-gradient NMR spectroscopy: application to myosin light chain 2.
1995,
Pubmed
Fan,
A novel conotoxin from Conus betulinus, kappa-BtX, unique in cysteine pattern and in function as a specific BK channel modulator.
2003,
Pubmed
Fletcher,
The structure of versutoxin (delta-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel.
1997,
Pubmed
Gray,
Disulfide structures of highly bridged peptides: a new strategy for analysis.
1993,
Pubmed
Herrmann,
Protein NMR structure determination with automated NOE assignment using the new software CANDID and the torsion angle dynamics algorithm DYANA.
2002,
Pubmed
Holm,
Touring protein fold space with Dali/FSSP.
1998,
Pubmed
Jimenez,
Novel excitatory Conus peptides define a new conotoxin superfamily.
2003,
Pubmed
Kauferstein,
A novel conotoxin inhibiting vertebrate voltage-sensitive potassium channels.
2003,
Pubmed
,
Xenbase
Kauferstein,
Direct cDNA cloning of novel conopeptide precursors of the O-superfamily.
2005,
Pubmed
Kauferstein,
Novel conopeptides of the I-superfamily occur in several clades of cone snails.
2004,
Pubmed
Kim,
Three-dimensional solution structure of the calcium channel antagonist omega-agatoxin IVA: consensus molecular folding of calcium channel blockers.
1995,
Pubmed
Koradi,
MOLMOL: a program for display and analysis of macromolecular structures.
1996,
Pubmed
Kuwada,
Omega-agatoxin-TK containing D-serine at position 46, but not synthetic omega-[L-Ser46]agatoxin-TK, exerts blockade of P-type calcium channels in cerebellar Purkinje neurons.
1994,
Pubmed
Laskowski,
AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR.
1996,
Pubmed
Maggio,
Scanning mutagenesis of a Janus-faced atracotoxin reveals a bipartite surface patch that is essential for neurotoxic function.
2002,
Pubmed
McIntosh,
A new family of conotoxins that blocks voltage-gated sodium channels.
1995,
Pubmed
Miles,
Structure of a novel P-superfamily spasmodic conotoxin reveals an inhibitory cystine knot motif.
2002,
Pubmed
Nicholls,
Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons.
1991,
Pubmed
Norton,
The cystine knot structure of ion channel toxins and related polypeptides.
1998,
Pubmed
Norton,
Conotoxins down under.
2006,
Pubmed
Olivera,
Conus peptides: biodiversity-based discovery and exogenomics.
2006,
Pubmed
Olivera,
Conotoxins, in retrospect.
2001,
Pubmed
Pallaghy,
Solution structure of robustoxin, the lethal neurotoxin from the funnel-web spider Atrax robustus.
1997,
Pubmed
Pallaghy,
A common structural motif incorporating a cystine knot and a triple-stranded beta-sheet in toxic and inhibitory polypeptides.
1994,
Pubmed
Rasband,
It's "juxta" potassium channel!
2004,
Pubmed
Reily,
The solution structure of omega-Aga-IVB, a P-type calcium channel antagonist from venom of the funnel web spider, Agelenopsis aperta.
1995,
Pubmed
Schwarz,
KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier.
2006,
Pubmed
Schwieters,
The Xplor-NIH NMR molecular structure determination package.
2003,
Pubmed
Seavey,
A relational database for sequence-specific protein NMR data.
1991,
Pubmed
Shon,
kappa-Conotoxin PVIIA is a peptide inhibiting the shaker K+ channel.
1998,
Pubmed
,
Xenbase
Terlau,
Conus venoms: a rich source of novel ion channel-targeted peptides.
2004,
Pubmed
Wang,
Discovery and characterization of a family of insecticidal neurotoxins with a rare vicinal disulfide bridge.
2000,
Pubmed
West,
Effects of delta-conotoxins PVIA and SVIE on sodium channels in the amphibian sympathetic nervous system.
2005,
Pubmed
Wishart,
1H, 13C and 15N random coil NMR chemical shifts of the common amino acids. I. Investigations of nearest-neighbor effects.
1995,
Pubmed
Yao,
Peptide self-association in aqueous trifluoroethanol monitored by pulsed field gradient NMR diffusion measurements.
2000,
Pubmed
Yu,
Sequential assignment and structure determination of spider toxin omega-Aga-IVB.
1993,
Pubmed
