ライフサイエンスコーパス: alpha-conotoxin

1 relationships for ImI as well other neuronal alpha-conotoxins.

2 folding motif may be common to a subclass of alpha-conotoxins.

3 cantly from those of all previously isolated alpha-conotoxins.

4 baclofen-sensitive Cav2.2 inhibition by the alpha-conotoxins.

5 -sensitive I(Ba) inhibition by the analgesic alpha-conotoxins.

6 bolished inhibition by both baclofen and the alpha-conotoxins.

7 s of the GABA(B)R subunits for the analgesic alpha-conotoxins.

8 ibition of the Ca(v)2.2 channel by analgesic alpha-conotoxins.

9 ree distinct gene families: mu-, omega-, and alpha-conotoxins.

10 of pl14a and the second loop of a number of alpha-conotoxins.

11 ges the prevailing understanding that native alpha-conotoxins adopt a globular conformation and illus

12 es between the two agonist sites for dTC and alpha-conotoxin (alpha Ctx) MI.

13 alpha-Conotoxin (alpha-Ctx) MII labeling coupled with im

14 We created analogs of alpha-conotoxin (alpha-Ctx) PeIA to identify ligand-rece

15 We previously showed that alpha-conotoxin (alpha-CTx) RgIA, one of the few alpha9a

16 The alpha-conotoxins (alpha-Ctxs) are short, disulfide-rich

17 Current alpha-conotoxins (alpha-Ctxs) that discriminate among th

18 Significantly, with more structures of alpha-conotoxins also becoming available this enables re

19 A second series of individual alpha-conotoxin analogs based on the combinations of def

20 Of the 96 individual alpha-conotoxin analogs synthesized, three displayed > o

21 RgIA) is a member of the alpha-4,3 family of alpha-conotoxins and selectively blocks the alpha9alpha1

22 Alpha-conotoxins are a group of small, structurally defi

23 Despite their small size, different alpha-conotoxins are able to discriminate among differen

24 Many new alpha-conotoxins are being identified every year, broade

25 alpha-Conotoxins are disulfide-rich peptide neurotoxins

26 alpha-Conotoxins are disulfide-rich peptides that are co

27 alpha-Conotoxins are extensively investigated for their

28 R residues involved in interactions with the alpha-conotoxins are K168 and R207 on the B2 subunit and

29 alpha-Conotoxins are nAChR-targeted peptides used by Con

30 alpha-Conotoxins are peptide neurotoxins isolated from v

31 alpha-Conotoxins are peptide toxins found in the venom o

32 alpha-Conotoxins are selective antagonists of neuromuscu

33 alpha-Conotoxins are small disulfide-constrained peptide

34 Alpha-conotoxins are small disulfide-constrained peptide

35 alpha-Conotoxins are subtype-selective nicotinic acetylc

36 alpha-Conotoxins are two-disulfide-bridged nicotinic ant

37 As selective alpha3beta4 nAChR antagonists, alpha-conotoxins are valuable tools to evaluate the func

38 pmol of a selective alpha7 nAChR antagonist, alpha-conotoxin ArIB [V11L,V16D] (ArIB) into the nucleus

39 alpha-Conotoxins, as nicotinic acetylcholine receptor (n

40 Finally, micro-infusion of alpha-conotoxin AuIB (10 mum) but not alpha-conotoxin MI

41 ontaining an alpha3/beta4 subunit interface (alpha-conotoxin AuIB 1 micrometer) resulted in attenuati

42 the alpha3beta4* nAChR-selective antagonist alpha-conotoxin AuIB almost completely abolished nicotin

43 alpha-Conotoxin AuIB blocks alpha3 beta4 nAChRs expresse

44 Furthermore, alpha-conotoxin AuIB blocks the alpha3 beta4 receptor wi

45 alpha-Conotoxin AuIB is a selective alpha3beta4 nicotini

46 alpha-Conotoxin AuIB, a potent antagonist of the alpha3b

47 ization of an alpha3 beta4 nAChR antagonist, alpha-conotoxin AuIB, from the venom of the "court cone,

48 lpha7 subunits (alphaBgt), and alpha3/beta4 (alpha-conotoxin-AuIB), or alpha3/beta2 (alpha-conotoxin-

49 te that these residues control access to the alpha-conotoxin binding site.

50 a positive charge in this position prevents alpha-conotoxin binding.

51 alpha-Conotoxin BuIA (500 nM) blocked acetylcholine-gate

52 Thus, alpha-conotoxin BuIA also represents a novel probe for d

53 Alpha-conotoxin BuIA kinetically distinguishes between b

54 Proline6 of alpha-conotoxin BuIA was found to be critical for nAChR

55 Block of [3H]norepinephrine release by alpha-conotoxin BuIA, a toxin that kinetically distingui

56 The resulting peptide, alpha-conotoxin BuIA, was tested on cloned nAChRs expres

57 alpha-Conotoxin BuIA[T5A;P6O] partially blocked norepine

58 from six Conus species: most (11/16) encoded alpha-conotoxins, but some (5/16) belong to a family of

59 this study, we designed cyclic analogues of alpha-conotoxin CIA, a potent muscle nicotinic acetylcho

60 natorial libraries in the discovery of novel alpha-conotoxin derivatives with refined pharmacological

61 a second generation library of 64 individual alpha-conotoxin derivatives.

62 -EIVA is similar to the previously described alpha-conotoxins (e.g. alpha-MI and alpha-GI) which also

63 onotoxin precursor, pro-GI, belonging to the alpha-conotoxin family.

64 gIA belongs to the alpha4/3 subfamily of the alpha-conotoxin family; sequence and subtype specificity

65 pecies that includes Conus radiatus uses the alphaS-conotoxin family to target the muscle nAChR and p

66 ere, we investigate the effects of analgesic alpha-conotoxins following the mutation of amino acid re

67 calculations predicted that all three of the alpha-conotoxins form close contacts with VFT residues i

68 covery and characterization of RoIA, a novel alpha-conotoxin from Conus rolani.

69 This study describes a novel alpha-conotoxin from the Western Atlantic species Conus

70 An alpha-conotoxin gene was cloned from Conus arenatus.

71 ChRs with a specific muscle nAChR inhibitor, alpha-conotoxin GI (alphaCTxGI), choline was used to act

72 nd in both of the two-step pathways by which alpha-conotoxin GI folds into its native structure at pH

73 for formation of the two disulfide bonds of alpha-conotoxin GI in pH 7.00 buffer and in pH 7.00 buff

74 alpha-Conotoxin GI is a 13 residue snail toxin peptide c

75 structural properties of Cono-1, Cono-2, and alpha-conotoxin GI were studied by 1H NMR to identify st

76 A cDNA clone encoding alpha-conotoxin GI, the first conotoxin characterized, p

77 ding some of the same secondary structure as alpha-conotoxin GI, which facilitates formation of the s

78 Cono-2 are considerably less structured than alpha-conotoxin GI, which indicates that formation of th

79 alpha-Conotoxins GI and MI are competitive antagonists o

80 However, neither alpha-conotoxin MII nor alpha-conotoxin GIC at concentrations of 10 microM block

81 Here we present the structure of alpha-conotoxin GIC in complex with Aplysia californica

82 ble efforts have been made to understand why alpha-conotoxin GIC is strongly selective for alpha3beta

83 Although alpha-conotoxin GIC shares some sequence similarity with

84 alpha-Conotoxin GIC shows no paralytic activity in fish

85 The toxin characterized in this report, alpha-conotoxin GIC, is a most striking exception.

86 Although potent alpha3beta2 nAChR-selective alpha-conotoxins have been identified, currently charact

87 obular connectivity, and previous studies of alpha-conotoxins have focused on the globular isomers as

88 alpha-Conotoxins have four cysteines that can have three

89 ously characterized C. imperialis conotoxin, alpha-conotoxin ImI (alpha-CTx ImI), is closely related;

90 The Conus peptides alpha-conotoxin ImI (alpha-ImI) and ImII (alpha-ImII) di

91 rating the alpha7-nicotinic receptor blocker alpha-conotoxin ImI (alpha-ImI) with polyethylene glycol

92 er well-characterized member of this family, alpha-conotoxin ImI (alpha-ImI), which is a potent inhib

93 The neuronal-specific toxin alpha-conotoxin ImI (CTx ImI) has the sequence Gly-Cys-C

94 The present work uses alpha-conotoxin ImI (CTx ImI) to probe the neurotransmit

95 ective for alpha1beta1gammadelta nAChRs) and alpha-conotoxin ImI (selective for alpha7-containing nAC

96 by mutagenesis studies and experiments with alpha-conotoxin ImI and a chimeric Naja oxiana alpha-neu

97 alpha-Conotoxin ImI and alpha-bungarotoxin-binding sites

98 alpha-Conotoxin ImI displayed inhibitory activity as wel

99 istep synthetic combinatorial approach using alpha-conotoxin ImI to develop potent and selective alph

100 based on the three residues of the n-loop of alpha-conotoxin ImI to give a total of 10,648 possible c

101 tructures and activities of three mutants of alpha-conotoxin ImI, a 12 amino acid peptide active at a

102 pens to accommodate the peptidic antagonist, alpha-conotoxin ImI, but wraps around the agonists lobel

103 ported the isolation and characterization of alpha-conotoxin ImI, which selectively targets homomeric

104 For alpha-conotoxins ImI and GI, the hydroxylation of the co

105 NMR solution structure of the smallest known alpha-conotoxin, ImI, a 12 amino acid peptide that binds

106 lpha7 nAChR antagonists (methyllycaconitine, alpha-conotoxin-ImI) and glutamate receptor (GluR) antag

107 A novel conotoxin, alpha-conotoxin ImII (alpha-CTx ImII), identified from C

108 study, we used a number of subtype-selective alpha-conotoxins in combination with nicotinic receptor

109 The alpha6-selective blocker, alpha-conotoxin, increased dopamine release in early ado

110 s simulations of homology models with docked alpha-conotoxin indicate that these residues control acc

111 e Venus flytrap (VFT) domains with which the alpha-conotoxins interact.

112 three-dimensional solution structure of the alpha-conotoxin Lo1a was determined by NMR spectroscopy.

113 We isolated an 18-amino acid peptide named alpha-conotoxin Lo1a, which is active on nAChRs.

114 ve ligands dimethyl-d-tubocurarine (DMT) and alpha-conotoxin M1 (CTX) confirm specificity of modifica

115 suggest different binding configurations of alpha-conotoxin M1 at the alpha-delta and alpha-gamma bi

116 We show by sedimentation analysis that 125I-alpha-conotoxin M1 binds with high affinity to the alpha

117 We also extend previous identification of alpha-conotoxin M1 determinants in the gamma and delta s

118 nd delta monomers, a finding consistent with alpha-conotoxin M1 selectivity for the alpha delta inter

119 f the gamma or delta subunits in stabilizing alpha-conotoxin M1.

120 actions underlying the nanomolar affinity of alpha-conotoxin MI (CTx MI) for the alpha-delta site of

121 rally related to alpha-conotoxin MII, namely alpha-conotoxin MI (selective for alpha1beta1gammadelta

122 Thus, alpha-conotoxin MI appears to interact with the portion

123 Unlike [(125)I]alpha-bungarotoxin, [(125)I]alpha-conotoxin MI binding to TE671 cell homogenates is

124 ed the importance of charge interactions for alpha-conotoxin MI binding to the nicotinic acetylcholin

125 ion experiments indicate that radioiodinated alpha-conotoxin MI binds to TE671 cell homogenates with

126 studies indicate that the binding of [(125)I]alpha-conotoxin MI is reversible (k(off) = 0.084 +/- 0.0

127 Alpha-conotoxin MI was subsequently radioiodinated, and

128 An analogue of alpha-conotoxin MI was synthesized with an iodine attach

129 Ionic residues on alpha-conotoxin MI were altered by site-directed mutagen

130 Alpha-Conotoxin MI, a 14-amino acid competitive antagoni

131 ite-selective antagonists d-tubocurarine and alpha-conotoxin MI.

132 ion of alpha-conotoxin AuIB (10 mum) but not alpha-conotoxin MII (10 mum) into the IPn in rats increa

133 Conversely, the alpha3 beta2-specific alpha-conotoxin MII (100 nM) blocks 33% of striatal dopa

134 alpha-Conotoxin MII (20 nM), dihydro-beta-erythroidine (

135 n of the alpha3beta2*/alpha6beta2* selective alpha-conotoxin MII (alpha-CTX MII) dose- and time-depen

136 w component was selectively blocked by 50 nM alpha-conotoxin MII (alpha-CTx-MII), which blocks mammal

137 In this study, we used a novel alpha-conotoxin MII (alpha-CtxMII) analog E11A to furthe

138 animals, alpha6beta2(*) nAChR blockade with alpha-conotoxin MII (alpha-CtxMII) decreased release wit

139 However, discovery that alpha-conotoxin MII (alpha-CtxMII) partially inhibits th

140 ially important in nicotine addiction, binds alpha-conotoxin MII (alpha-CtxMII) with high affinity an

141 re pharmacologically similar to native [125I]alpha-conotoxin MII (alpha-CtxMII)-binding and 3-(2(S)-a

142 alpha-Conotoxin MII (CtxMII), a peptide toxin from the v

143 For this purpose we used (125)I-alpha-conotoxin MII (CtxMII), a relatively new ligand th

144 Binding of [(125)I]alpha-conotoxin MII (largely to alpha6* nAChRs) did not

145 ster (RTI-121, dopamine transporter), (125)I-alpha-conotoxin MII (putative alpha 6-containing sites i

146 ontaining an alpha3/beta2 subunit interface (alpha-conotoxin MII 100-200 nm) resulted in reversible a

147 Intriguingly, alpha-conotoxin MII [H9A; L15A], blocked cocaine conditi

148 mbal injection of the selective alpha6beta2* alpha-conotoxin MII [H9A; L15A], blocked nicotine CPP.

149 bition constant of MII[H9A;L15A] for [(125)I]alpha-conotoxin MII binding to putative alpha6beta2(*) n

150 ies for nicotine, cytisine, and A85380, that alpha-conotoxin MII discriminates between nAChR populati

151 Thus, structure-function analysis of alpha-conotoxin MII enabled the creation of novel select

152 Whereas alpha-conotoxin MII fully inhibits nicotine-evoked [3H]n

153 The three-dimensional structure of alpha-conotoxin MII in aqueous solution has been determi

154 e (IR) binding of either labeled Epb or 125I-alpha-conotoxin MII increased to a much greater extent t

155 The recently discovered peptide alpha-conotoxin MII is a potent and selective inhibitor

156 The alpha3/alpha6-selective antagonist alpha-conotoxin MII maximally inhibited 50% of binding i

157 which seemed to be due to a complete loss of alpha-conotoxin MII nAChRs and a partial loss of other n

158 However, neither alpha-conotoxin MII nor alpha-conotoxin GIC at concentra

159 the alpha3beta2* nAChR-selective antagonist alpha-conotoxin MII only partially attenuated these curr

160 Structure-function analysis of alpha-conotoxin MII was performed in an attempt to gener

161 isine, (125)I-alpha-bungarotoxin, and (125)I-alpha-conotoxin MII) suggest the following: that alpha6b

162 Alpha-conotoxin MII, a peptide toxin isolated from Conus

163 Alpha-conotoxin MII, a selective ligand that discriminat

164 , 5-iodo-A-85380, sazetidine-A, varenicline, alpha-conotoxin MII, and bPiDDB (N,N-dodecane-1,12-diyl-

165 alpha-Conotoxin MII, isolated from Conus magus, is a pot

166 ermore, two peptides structurally related to alpha-conotoxin MII, namely alpha-conotoxin MI (selectiv

167 This peptide, named alpha-conotoxin MII, was identified by electrophysiologi

168 xin GIC shares some sequence similarity with alpha-conotoxin MII, which is also a potent alpha3beta2

169 to identify a population of beta3-dependent alpha-conotoxin MII-binding nAChRs that modulate striata

170 ve nAChRs, and selected measures of striatal alpha-conotoxin MII-resistant nAChRs.

171 ed striatal dopamine release (both total and alpha-conotoxin MII-resistant release) increased with ag

172 tigated and did not discriminate between the alpha-conotoxin MII-sensitive and -insensitive populatio

173 lations in the caudate and putamen, and that alpha-conotoxin MII-sensitive nAChRs are selectively dec

174 binding and functional measures of striatal alpha-conotoxin MII-sensitive nAChRs, and selected measu

175 se in epibatidine binding was due to loss of alpha-conotoxin MII-sensitive nAChRs.

176 d with the alpha3beta2-preferring antagonist alpha-conotoxin MII.

177 y itself, but not in animals pretreated with alpha-conotoxin MII.

178 alpha-conotoxin MII[H9A;L15A] also significantly reduced

179 t in VTA DAergic neurons that was blocked by alpha-conotoxin MII[H9A;L15A], a selective antagonist of

180 lasted several minutes and was sensitive to alpha-conotoxin MII[H9A;L15A].

181 pha-conotoxin PeIA bears high resemblance to alpha-conotoxins MII and GIC isolated from Conus magus a

182 nt of the giant fiber system is inhibited by alpha-conotoxins MII, AuIB, BuIA, EI, PeIA, and ImI.

183 these mutants revealed increased affinity of alpha-conotoxins MII, TxIA, and [A10L]TxIA at the alpha4

184 The competitive antagonist alpha-conotoxin-MII (alpha-CTx-MII) is highly selective

185 (EC(50) = 1.2 microM) that was unaffected by alpha-conotoxin-MII or dihydro-beta-erythroidine, antago

186 ta4 (alpha-conotoxin-AuIB), or alpha3/beta2 (alpha-conotoxin-MII) subunit interfaces to perturb respo

187 As such, alpha-conotoxins offer the potential to become templates

188 ty for the alpha3beta2 nAChR indicating that alpha-conotoxin OmIA in combination with the AChBP may s

189 alpha-Conotoxin OmIA was purified from the venom of Conu

190 The effects of baclofen and alpha-conotoxins on the peak Ba(2+) current (I(Ba)) ampl

191 Alpha-conotoxin PeIA bears high resemblance to alpha-con

192 Alpha-conotoxin PeIA displayed a 260-fold higher selecti

193 Alpha-conotoxin PeIA represents a novel probe to differe

194 hesis, and characterization of a novel toxin alpha-conotoxin PeIA that discriminates between alpha9al

195 non-alpha-bungarotoxin-sensitive receptors, alpha-conotoxin PeIA was also active at alpha3beta2 rece

196 We used positional scanning mutagenesis of alpha-conotoxin PeIA, which targets both alpha6beta2* an

197 esized novel analogs of a recently described alpha-conotoxin, PeIA.

198 Alpha-Conotoxins, peptides produced by predatory species

199 The predicted peptide, alpha-conotoxin PIA, potently blocks the chimeric alpha6

200 minal segment of the helix-promoting peptide alpha-conotoxin pl14a.

201 peptides from the venom of Conus pennaceus, alpha-conotoxins PnIA and PnIB, are examined.

202 of ImI to those of the larger, 16 amino acid alpha-conotoxins PnIA, PnIB, MII, and EpI-also specific

203 This work uses alpha-conotoxin PnIB to probe the agonist binding site o

204 ly of alpha7beta2-nAChR-selective analogs of alpha-conotoxin PnIC (alpha-CtxPnIC).

205 te but in loop C completely transferred high alpha-conotoxin potency to the alpha4beta2 receptor.

206 Conversely, alpha-conotoxin potency was reduced at the reverse alpha

207 Native alpha-conotoxins preferably adopt the globular connectiv

208 of Acapital ES, CyrillichBP in complex with alpha-conotoxins provide important insights into the int

209 Thus, it is increasingly apparent that alpha-conotoxins represent a significant resource for li

210 The 13-residue peptide alpha-conotoxin RgIA (alpha-RgIA) is a member of the alp

211 m the Western Atlantic species Conus regius, alpha-conotoxin RgIA (alpha-RgIA), that is a subtype spe

212 alpha-Conotoxin RgIA is both an antagonist of the alpha9

213 10 nAChR antagonists, alpha-bungarotoxin and alpha-conotoxin RgIA, blocked efferent-mediated inhibiti

214 The peptide, alphaS-conotoxin RVIIIA (alphaS-RVIIIA), is biochemicall

215 Yet other alpha-conotoxins selectively block the muscle subtype of

216 ave been identified, currently characterized alpha-conotoxins show no or only weak affinity for alpha

217 In contrast, alpha-conotoxin SI does not distinguish between the two

218 Four analogues of the natural regioisomer of alpha-conotoxin SI were designed and synthesized, each w

219 Replacement of the Cys(2)-Cys(7) loop of alpha-conotoxin SI with a lactam bridge resulted in comp

220 preparation of bicyclic lactam analogues of alpha-conotoxin SI, a 13-residue peptide neurotoxin foun

221 In the present study, alpha-conotoxin SIA also displayed strong affinity for t

222 Using conserved features of the alpha-conotoxin signal sequence and 3'-untranslated sequ

223 alpha-Conotoxin SII was shown to possess 3-8, 2-18, and

224 us assignment of disulfide connectivities in alpha-conotoxin SII, of which approximately 30% of its m

225 eses regarding the molecular determinants of alpha-conotoxin specificity are not adequate for explain

226 tertiary structural requirements of neuronal alpha-conotoxin specificity.

227 ort the isolation and characterization of an alpha-conotoxin that has the highest known affinity for

228 venom of Conus brunneus, we found BruIB, an alpha-conotoxin that inhibits Drosophila nicotinic recep

229 ockade) or 500 nM PnIA (23.0+/-4% blockade), alpha-conotoxins that target alpha7 and alpha3beta2*/alp

230 er 300 nM BuIA[T5A;P6O] or 200 nM MII[E11A], alpha-conotoxins that target the alpha6beta4* subtype, b

231 trast to the 12-18 residue, 4 Cys-containing alpha-conotoxins, the new toxins have 30 residues and 6

232 rophysiology together with subtype-selective alpha-conotoxins to pharmacologically characterize the n

233 B)R involved in the binding of the analgesic alpha-conotoxins to the VFT domains of the GABA(B)R.

234 y alpha-bungarotoxin but were insensitive to alpha-conotoxin [V11L;V16D]ArIB and RgIA-5474, which pot

235 lectrophysiology, and mutagenesis, we showed alpha-conotoxin Vc1.1 modulates Cav2.2 via a different p

236 alpha-Conotoxin Vc1.1 specifically and potently inhibits

237 Analgesic alpha-conotoxin Vc1.1, a peptide from predatory marine c

238 peptides, including the cyclotide kalata B1, alpha-conotoxin Vc1.1, and sunflower trypsin inhibitor 1

239 alpha-Conotoxins Vc1.1 and RgIA are small peptides isola

240 e effect of the GABA(B) agonist baclofen and alpha-conotoxins Vc1.1 and RgIA on calcium channel curre

241 ype (Ca(v)2.2) calcium channels by analgesic alpha-conotoxins Vc1.1 and RgIA.

242 The analgesic alpha-conotoxins Vc1.1, RgIA, and PeIA attenuate nocicep

243 dy defines the binding site of the analgesic alpha-conotoxins Vc1.1, RgIA, and PeIA on the human GABA

244 gic pathways can be selectively inhibited by alpha-conotoxins; we show that in the model organism Dro

245 Point mutation chimeras of these alpha-conotoxins were synthesized and their activities a

246 The ligand is the first alpha-conotoxin with higher affinity for the closely rel

247 ; the gene codes for a previously unreported alpha-conotoxin with unusual 4/4 spacing of amino acids

248 important insights into the interactions of alpha-conotoxins with distinct nAChR subtypes.