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.
Biochemistry
2008 Oct 14;4741:10940-9. doi: 10.1021/bi801010u.
Show Gene links
Show Anatomy links
Structure, dynamics, and selectivity of the sodium channel blocker mu-conotoxin SIIIA.
Yao S
,
Zhang MM
,
Yoshikami D
,
Azam L
,
Olivera BM
,
Bulaj G
,
Norton RS
.
???displayArticle.abstract???
mu-SIIIA, a novel mu-conotoxin from Conus striatus, appeared to be a selective blocker of tetrodotoxin-resistant sodium channels in frog preparations. It also exhibited potent analgesic activity in mice, although its selectivity profile against mammalian sodium channels remains unknown. We have determined the structure of mu-SIIIA in aqueous solution and characterized its backbone dynamics by NMR and its functional properties electrophysiologically. Consistent with the absence of hydroxyprolines, mu-SIIIA adopts a single conformation with all peptide bonds in the trans conformation. The C-terminal region contains a well-defined helix encompassing residues 11-16, while residues 3-5 in the N-terminal region form a helix-like turn resembling 3 10-helix. The Trp12 and His16 side chains are close together, as in the related conotoxin mu-SmIIIA, but Asn2 is more distant. Dynamics measurements show that the N-terminus and Ser9 have larger-magnitude motions on the subnanosecond time scale, while the C-terminus is more rigid. Cys4, Trp12, and Cys13 undergo significant conformational exchange on microsecond to millisecond time scales. mu-SIIIA is a potent, nearly irreversible blocker of Na V1.2 but also blocks Na V1.4 and Na V1.6 with submicromolar potency. The selectivity profile of mu-SIIIA, including poor activity against the cardiac sodium channel, Na V1.5, is similar to that of the closely related mu-KIIIA, suggesting that the C-terminal regions of both are critical for blocking neuronal Na V1.2. The structural and functional characterization described in this paper of an analgesic mu-conotoxin that targets neuronal subtypes of mammalian sodium channels provides a basis for the design of novel analogues with an improved selectivity profile.
Atkinson,
Reduced spectral density mapping for proteins: Validity for studies of 13C relaxation.
1999, Pubmed
Atkinson,
Reduced spectral density mapping for proteins: Validity for studies of 13C relaxation.
1999,
Pubmed
Atkinson,
Structural and dynamic characterization of omega-conotoxin MVIIA: the binding loop exhibits slow conformational exchange.
2000,
Pubmed
Baell,
Design and synthesis of type-III mimetics of omega-conotoxin GVIA.
2001,
Pubmed
Bartels,
The program XEASY for computer-supported NMR spectral analysis of biological macromolecules.
1995,
Pubmed
Buczek,
Structure and sodium channel activity of an excitatory I1-superfamily conotoxin.
2007,
Pubmed
,
Xenbase
Bulaj,
Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels.
2005,
Pubmed
Catterall,
From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels.
2000,
Pubmed
Cestèle,
Molecular mechanisms of neurotoxin action on voltage-gated sodium channels.
2000,
Pubmed
Cornilescu,
Protein backbone angle restraints from searching a database for chemical shift and sequence homology.
1999,
Pubmed
Cruz,
Conus geographus toxins that discriminate between neuronal and muscle sodium channels.
1985,
Pubmed
Eisenmesser,
Enzyme dynamics during catalysis.
2002,
Pubmed
Ellison,
Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues.
2008,
Pubmed
Farrow,
Backbone dynamics of a free and phosphopeptide-complexed Src homology 2 domain studied by 15N NMR relaxation.
1994,
Pubmed
Feher,
Millisecond-timescale motions contribute to the function of the bacterial response regulator protein Spo0F.
1999,
Pubmed
Fiedler,
Specificity, affinity and efficacy of iota-conotoxin RXIA, an agonist of voltage-gated sodium channels Na(V)1.2, 1.6 and 1.7.
2008,
Pubmed
,
Xenbase
Frauenfelder,
Conformational substates in proteins.
1988,
Pubmed
Goldenberg,
Solution structure and backbone dynamics of an omega-conotoxin precursor.
2001,
Pubmed
Goldin,
Resurgence of sodium channel research.
2001,
Pubmed
Green,
Conotoxins containing nonnatural backbone spacers: cladistic-based design, chemical synthesis, and improved analgesic activity.
2007,
Pubmed
Herrmann,
Protein NMR structure determination with automated NOE assignment using the new software CANDID and the torsion angle dynamics algorithm DYANA.
2002,
Pubmed
Hill,
Three-dimensional solution structure of mu-conotoxin GIIIB, a specific blocker of skeletal muscle sodium channels.
1996,
Pubmed
Hyberts,
The solution structure of eglin c based on measurements of many NOEs and coupling constants and its comparison with X-ray structures.
1992,
Pubmed
Jones,
Conotoxins - new vistas for peptide therapeutics.
2000,
Pubmed
Keizer,
Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA.
2003,
Pubmed
Koradi,
MOLMOL: a program for display and analysis of macromolecular structures.
1996,
Pubmed
Lancelin,
Tertiary structure of conotoxin GIIIA in aqueous solution.
1991,
Pubmed
Laskowski,
AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR.
1996,
Pubmed
Lewis,
Isolation and structure-activity of mu-conotoxin TIIIA, a potent inhibitor of tetrodotoxin-sensitive voltage-gated sodium channels.
2007,
Pubmed
,
Xenbase
Li,
Molecular basis of isoform-specific micro-conotoxin block of cardiac, skeletal muscle, and brain Na+ channels.
2003,
Pubmed
Mandel,
Dynamics of ribonuclease H: temperature dependence of motions on multiple time scales.
1996,
Pubmed
Mandel,
Backbone dynamics of Escherichia coli ribonuclease HI: correlations with structure and function in an active enzyme.
1995,
Pubmed
Moczydlowski,
Discrimination of muscle and neuronal Na-channel subtypes by binding competition between [3H]saxitoxin and mu-conotoxins.
1986,
Pubmed
Nielsen,
Structure-activity relationships of omega-conotoxins at N-type voltage-sensitive calcium channels.
2000,
Pubmed
Nielsen,
Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels.
2002,
Pubmed
Norton,
Conotoxins down under.
2006,
Pubmed
Norton,
Studies of proteins in solution by natural-abundance carbon-13 nuclear magnetic resonance. Spectral resolution and relaxation behavior at high magnetic field strengths.
1977,
Pubmed
Oldfield,
Studies of individual carbon sites of proteins in solution by natural abundance carbon 13 nuclear magnetic resonance spectroscopy. Relaxation behavior.
1975,
Pubmed
Otting,
Disulfide bond isomerization in BPTI and BPTI(G36S): an NMR study of correlated mobility in proteins.
1993,
Pubmed
Pallaghy,
Three-dimensional structure in solution of the calcium channel blocker omega-conotoxin.
1993,
Pubmed
Palmer,
Probing molecular motion by NMR.
1997,
Pubmed
Robinson,
Microwave-assisted RCM for the synthesis of carbocyclic peptides.
2007,
Pubmed
Safo,
Distinction among neuronal subtypes of voltage-activated sodium channels by mu-conotoxin PIIIA.
2000,
Pubmed
,
Xenbase
Schwieters,
The Xplor-NIH NMR molecular structure determination package.
2003,
Pubmed
Shon,
mu-Conotoxin PIIIA, a new peptide for discriminating among tetrodotoxin-sensitive Na channel subtypes.
1998,
Pubmed
Slupsky,
Probing nascent structures in peptides using natural abundance 13C NMR relaxation and reduced spectral density mapping.
2007,
Pubmed
Ulrich,
BioMagResBank.
2008,
Pubmed
Volkman,
Two-state allosteric behavior in a single-domain signaling protein.
2001,
Pubmed
Wakamatsu,
Structure-activity relationships of mu-conotoxin GIIIA: structure determination of active and inactive sodium channel blocker peptides by NMR and simulated annealing calculations.
1992,
Pubmed
Wei,
Solid-state (13)C NMR chemical shift anisotropy tensors of polypeptides.
2001,
Pubmed
West,
Mu-conotoxin SmIIIA, a potent inhibitor of tetrodotoxin-resistant sodium channels in amphibian sympathetic and sensory neurons.
2002,
Pubmed
Zhang,
Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels.
2007,
Pubmed
,
Xenbase
