| Structural highlights
Function
[WGRTX_GRARO] Inhibits P/Q- (Cav2.1/CACNA1A) and N-type (Cav2.2/CACNA1B) voltage-gated calcium channel by modifying voltage-dependent gating. It selectively and reversibly blocks the calcium channels coupled to glutamate release. Also inhibits potassium channels (Kv2.1/KCNB1) with lower affinity.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
omega-Grammotoxin SIA (GrTx) is a 36 amino acid residue protein toxin from spider venom that inhibits P/Q and N-type voltage-gated Ca(2+) channels by modifying voltage-dependent gating. We determined the three-dimensional structure of GrTx using NMR spectroscopy. The toxin adopts an "inhibitor cystine knot" motif composed of two beta-strands (Leu19-Cys21 and Cys30-Trp32) and a beta-bulge (Trp6, Gly7-Cys30) with a +2x, -1 topology, which are connected by four chain reversals. Although GrTx was originally identified as an inhibitor of voltage-gated Ca(2+) channel, it also binds to K(+) channels with lower affinity. A similar cross-reaction was observed for Hanatoxin1 (HaTx), which binds to the voltage-sensing domains of K(+) and Ca(2+) channels with different affinities. A detailed comparison of the GrTx and HaTx structures identifies a conserved face containing a large hydrophobic patch surrounded by positively charged residues. The slight differences in the surface shape, which result from the orientation of the surface aromatic residues and/or the distribution of the charged residues, may explain the differences in the binding affinity of these gating modifiers with different voltage-gated ion channels.
Solution structure of omega-grammotoxin SIA, a gating modifier of P/Q and N-type Ca(2+) channel.,Takeuchi K, Park E, Lee C, Kim J, Takahashi H, Swartz K, Shimada I J Mol Biol. 2002 Aug 16;321(3):517-26. PMID:12162963[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ono S, Kimura T, Kubo T. Characterization of voltage-dependent calcium channel blocking peptides from the venom of the tarantula Grammostola rosea. Toxicon. 2011 Sep 1;58(3):265-76. doi: 10.1016/j.toxicon.2011.06.006. Epub 2011, Jun 28. PMID:21740921 doi:http://dx.doi.org/10.1016/j.toxicon.2011.06.006
- ↑ Lampe RA, Defeo PA, Davison MD, Young J, Herman JL, Spreen RC, Horn MB, Mangano TJ, Keith RA. Isolation and pharmacological characterization of omega-grammotoxin SIA, a novel peptide inhibitor of neuronal voltage-sensitive calcium channel responses. Mol Pharmacol. 1993 Aug;44(2):451-60. PMID:8394998
- ↑ Piser TM, Lampe RA, Keith RA, Thayer SA. Complete and reversible block by omega-grammotoxin SIA of glutamatergic synaptic transmission between cultured rat hippocampal neurons. Neurosci Lett. 1995 Dec 8;201(2):135-8. PMID:8848236
- ↑ McDonough SI, Lampe RA, Keith RA, Bean BP. Voltage-dependent inhibition of N- and P-type calcium channels by the peptide toxin omega-grammotoxin-SIA. Mol Pharmacol. 1997 Dec;52(6):1095-104. PMID:9415720
- ↑ Li-Smerin Y, Swartz KJ. Gating modifier toxins reveal a conserved structural motif in voltage-gated Ca2+ and K+ channels. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8585-9. PMID:9671721
- ↑ Takeuchi K, Park E, Lee C, Kim J, Takahashi H, Swartz K, Shimada I. Solution structure of omega-grammotoxin SIA, a gating modifier of P/Q and N-type Ca(2+) channel. J Mol Biol. 2002 Aug 16;321(3):517-26. PMID:12162963
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