Solution structure of omega-grammotoxin SIA, a gating modifier of P/Q and N-type Ca(2+) channel.
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.
Takeuchi
Koh
K
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 113-0033, Tokyo, Japan.
Park
Eun
E
Lee
Chul
C
Kim
Jae
J
Takahashi
Hideo
H
Swartz
Kenton
K
Shimada
Ichio
I
D000595:Amino Acid Sequence; D000818:Animals; D020864:Calcium Channels, N-Type / Q000187:drug effects* / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D011817:Rabbits; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013111:Spider Venoms; D014982:Xenopus laevis
D020864:Calcium Channels, N-Type; D010456:Peptides, Cyclic; D013111:Spider Venoms; C082807:omega-grammotoxin SIA