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
2009 Feb 17;486:1210-9. doi: 10.1021/bi801998a.
Show Gene links
Show Anatomy links
Structure of the analgesic mu-conotoxin KIIIA and effects on the structure and function of disulfide deletion.
Khoo KK, Feng ZP, Smith BJ, Zhang MM, Yoshikami D, Olivera BM, Bulaj G, Norton RS.
???displayArticle.abstract???
Mu-conotoxin mu-KIIIA, from Conus kinoshitai, blocks mammalian neuronal voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. We have determined its solution structure using NMR spectroscopy. Key residues identified previously as being important for activity against VGSCs (Lys7, Trp8, Arg10, Asp11, His12, and Arg14) all reside on an alpha-helix with the exception of Arg14. To further probe structure-activity relationships of this toxin against VGSC subtypes, we have characterized the analogue mu-KIIIA[C1A,C9A], in which the Cys residues involved in one of the three disulfides in mu-KIIIA were replaced with Ala. Its structure is quite similar to that of mu-KIIIA, indicating that the Cys1-Cys9 disulfide bond could be removed without any significant distortion of the alpha-helix bearing the key residues. Consistent with this, mu-KIIIA[C1A,C9A] retained activity against VGSCs, with its rank order of potency being essentially the same as that of mu-KIIIA, namely, Na(V)1.2 > Na(V)1.4 > Na(V)1.7 >or= Na(V)1.1 > Na(V)1.3 > Na(V)1.5. Kinetics of block were obtained for Na(V)1.2, Na(V)1.4, and Na(V)1.7, and in each case, both k(on) and k(off) values of mu-KIIIA[C1A,C9A] were larger than those of mu-KIIIA. Our results show that the key residues for VGSC binding lie mostly on an alpha-helix and that the first disulfide bond can be removed without significantly affecting the structure of this helix, although the modification accelerates the on and off rates of the peptide against all tested VGSC subtypes. These findings lay the groundwork for the design of minimized peptides and helical mimetics as novel analgesics.
Barnham,
Role of the 6-20 disulfide bridge in the structure and activity of epidermal growth factor.
1998, Pubmed
Barnham,
Role of the 6-20 disulfide bridge in the structure and activity of epidermal growth factor.
1998,
Pubmed Bartels,
The program XEASY for computer-supported NMR spectral analysis of biological macromolecules.
1995,
Pubmed Bayrhuber,
Conkunitzin-S1 is the first member of a new Kunitz-type neurotoxin family. Structural and functional characterization.
2005,
Pubmed Bulaj,
Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels.
2005,
Pubmed Bulaj,
Synthetic muO-conotoxin MrVIB blocks TTX-resistant sodium channel NaV1.8 and has a long-lasting analgesic activity.
2006,
Pubmed Carrega,
The impact of the fourth disulfide bridge in scorpion toxins of the alpha-KTx6 subfamily.
2005,
Pubmed Catterall,
Voltage-gated ion channels and gating modifier toxins.
2007,
Pubmed Cummins,
The roles of sodium channels in nociception: Implications for mechanisms of pain.
2007,
Pubmed Dingley,
Measuring protein self-association using pulsed-field-gradient NMR spectroscopy: application to myosin light chain 2.
1995,
Pubmed Ellison,
Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues.
2008,
Pubmed Fiser,
Modeller: generation and refinement of homology-based protein structure models.
2003,
Pubmed Flinn,
Role of disulfide bridges in the folding, structure and biological activity of omega-conotoxin GVIA.
1999,
Pubmed French,
Sodium channel toxins--receptor targeting and therapeutic potential.
2004,
Pubmed Green,
Conotoxins containing nonnatural backbone spacers: cladistic-based design, chemical synthesis, and improved analgesic activity.
2007,
Pubmed Han,
Structurally minimized mu-conotoxin analogues as sodium channel blockers: implications for designing conopeptide-based therapeutics.
2009,
Pubmed
,
Xenbase Han,
Conus venoms - a rich source of peptide-based therapeutics.
2008,
Pubmed Herrmann,
Protein NMR structure determination with automated NOE-identification in the NOESY spectra using the new software ATNOS.
2002,
Pubmed Jorgensen,
The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin.
1988,
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 Laskowski,
AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR.
1996,
Pubmed Leipold,
muO conotoxins inhibit NaV channels by interfering with their voltage sensors in domain-2.
2007,
Pubmed Merutka,
'Random coil' 1H chemical shifts obtained as a function of temperature and trifluoroethanol concentration for the peptide series GGXGG.
1995,
Pubmed Norton,
Conotoxins down under.
2006,
Pubmed Pennington,
Role of disulfide bonds in the structure and potassium channel blocking activity of ShK toxin.
1999,
Pubmed
,
Xenbase Piotto,
Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions.
1992,
Pubmed Schmalhofer,
ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors.
2008,
Pubmed Schroeder,
Neuronally micro-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels.
2008,
Pubmed
,
Xenbase Schwieters,
The Xplor-NIH NMR molecular structure determination package.
2003,
Pubmed Seavey,
A relational database for sequence-specific protein NMR data.
1991,
Pubmed Sokolov,
Inhibition of sodium channel gating by trapping the domain II voltage sensor with protoxin II.
2008,
Pubmed
,
Xenbase Wang,
A novel conotoxin from Conus striatus, mu-SIIIA, selectively blocking rat tetrodotoxin-resistant sodium channels.
2006,
Pubmed West,
Mu-conotoxin SmIIIA, a potent inhibitor of tetrodotoxin-resistant sodium channels in amphibian sympathetic and sensory neurons.
2002,
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,
Structure, dynamics, and selectivity of the sodium channel blocker mu-conotoxin SIIIA.
2008,
Pubmed
,
Xenbase Yao,
Peptide self-association in aqueous trifluoroethanol monitored by pulsed field gradient NMR diffusion measurements.
2000,
Pubmed Zhang,
Structural and functional diversities among mu-conotoxins targeting TTX-resistant sodium channels.
2006,
Pubmed Zhang,
Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels.
2007,
Pubmed
,
Xenbase Zhang,
Synergistic and antagonistic interactions between tetrodotoxin and mu-conotoxin in blocking voltage-gated sodium channels.
2009,
Pubmed
,
Xenbase
