Structure-activity relationships of .mu.-conotoxin GIIIA: structure determination of active and inactive sodium channel blocker peptides by NMR and simulated annealing calculations

Neuronally Selective μ-Conotoxins from Conus striatus Utilize an α-Helical Motif to Target Mammalian Sodium Channels

“…GIIIA, GIIIB, PIIIA, SmIIIA, and TIIIA each comprise a series of turns and loops (14,15,17,25,27,42), with a ␤-hairpin seen in the N-terminal part of GIIIA and GIIIB and the minor conformation of PIIIA (14). These turns in GIIIB, SmIIIA, PIIIA, and TIIIA produce a 3 10 -helix across residues 13-22, 13-20, 13-17, and 12-15, respectively (numbering specific to each conotoxin) (14,15,17,25,27,42) compared with the ␣-helix found in SIIIA. Previously described structures of SIIIA and KIIIA (18,20,21), as well as CnIIIA, CnIIIB, CIIIA, and MIIIA (21), were modeled from the NMR structure of SmIIIA (17).…”

“…Lastly, -conotoxins CnIIIA, CnIIIB from Conus consors, CIIIA from Conus catus, and MIIIA from Conus magus were found to inhibit TTX-R and TTX-S sodium channels in frog DRG but not rat or mouse DRG neurons (21). Most reported -conotoxins have a conserved arginine in loop 2, which is essential for high affinity interactions at TTX-S sodium channels (15,(22)(23)(24)(25). In contrast, SIIIA and KIIIA have a much shorter loop 2 and a lysine instead of an arginine in the corresponding position.…”

Structure-Activity Relationships of Hainantoxin-IV and Structure Determination of Active and Inactive Sodium Channel Blockers

“…2A shows the best fit superposition of the backbone atoms (N, C ␣ , and C) for the 20 converged structures of native HNTX-IV. Analysis of the 20 converged structures indicated that the molecular structure of HNTX-IV contained a short triple-stranded antiparallel ␤-sheet formed by the strands Lys 7 -Cys 9 , Leu 22 -Ser 25 and Trp 30 -Tyr 33 , respectively (Fig. 2B).…”

Clockwise Domain Arrangement of the Sodium Channel Revealed by ¼-Conotoxin (GIIIA) Docking Orientation

“…They are peptides consisting of 22 amino acid residues with six cysteines that form three intramolecular disulfide bonds, imparting backbone rigidity (2-7, 10 -11). Their three-dimensional structures are well defined (12)(13)(14), making -CTXs useful probes to study the Na ϩ channel pore structure. Unlike tetrodotroxin and saxitoxin, whose smaller sizes render their receptor sites more compact (15)(16)(17)(18)(19)(20), high-affinity binding of -CTXs results from the summed effects of numerous weaker toxin-channel interactions (9,(21)(22)(23).…”

“…This notion is supported by the findings that critical channel residues for -CTX block identified to date are mostly clustered in domain II (DII), while "homologous" residues in other domains often have less or no effect (9, 30 -32). Previously, Chang et al (32) demonstrated that the toxin residue Arg 13 , which is required to inhibit current flow, interacts intimately with the DII pore residue Glu 758 . Based on this observation, the estimated dimensions of the channel pore, and the known structure of the toxin, these authors proposed that -CTX docks like an inverted pyramid with Arg 13 reaching the deep pore region.…”