Vc1.1 (P00004) Protein Card

General Information
Name Vc1.1
Alternative name(s) ACV1
Organism synthetic construct
Protein Type Synthetic
Parent VcIA
Notes

Inhibition of N-type Ca2+ channel current through the GABAB in rat DRG neurons with an IC50 of 1.7nM (Callaghan et al. 2008) and 24.6nM in mouse DRG of an a9 KO mouse (Callaghan et al. 2010). The specific receptor remains unclear.

Tabassum et al. 2017 reported that Vc1.1 is a potent inhibitor of hα9α10 and hα3β2 nAChRs, with complete inhibition observed at 10 μM.


Classification
Conopeptide class conotoxin
Gene superfamily
Cysteine framework I
Pharmacological family alpha conotoxin

Sequence
GCCSDPRCNYDHPEIC(nh2)
Modified residues
positionsymbolname
17nh2C-term amidation
Average Mass 1806.97
Monoisotopic Mass 1805.64
Isoelectric Point 5.63
Extinction Coefficient [280nm] 1490.00

Activity

IC50: Voltage-Gated Calcium Channels

TargetOrganismIC50nhillAgonistRef
Cav2.2H. sapiens(GABABR-coupled CaV2.2)2.4 nM[0.8-7]Cai,F. et al. (2018)

IC50: Nicotinic acetylcholine receptors

TargetOrganismIC50nhillAgonistRef
α1β1γδR. norvegicus>30uMAchClark,R.J. et al. (2006)
α3α5β2R. norvegicus7.2uM+/-0.21.3AchClark,R.J. et al. (2006)
α3α5β4R. norvegicus>30uMAchClark,R.J. et al. (2006)
α3β2R. norvegicus>1uM30-100mM AchSafavi-Hemami,H. et al. (2011)
5.5uM10uM AchHalai,R. et al. (2009)
7.3uM+/-0.71.7AchClark,R.J. et al. (2006)
α3β4R. norvegicus4.2uM+/-1.61.3AchClark,R.J. et al. (2006)
>3uM10uM AchHalai,R. et al. (2009)
α4β2R. norvegicus>30uMAchClark,R.J. et al. (2006)
α4β4R. norvegicus>30uMAchClark,R.J. et al. (2006)
α6/α3β2β3R. norvegicus140nM100uM AchVincler,M. et al. (2006)
α6/α3β4R. norvegicus980nM100uM AchVincler,M. et al. (2006)
α7H. sapiens>10 000 nMAch (100 uM)Liang,J. et al. (2020)
R. norvegicus7.1uM10uM AchHalai,R. et al. (2009)
>30uMAchClark,R.J. et al. (2006)
>1uM30-100mM AchSafavi-Hemami,H. et al. (2011)
α9α10H. sapiens(mutant α9[N154G]α10 α9:α10 subunit ratio of 1:3)11.25 uM+/-1.5Ach (6 uM)Yu,R. et al. (2018)
(α9:α10 subunit ratio of 1:3)3.57 uM+/-0.31Ach (6 uM)Yu,R. et al. (2018)
(human a9 rat a10)549nM10uM AchHalai,R. et al. (2009)
(α9:α10 subunit ratio of 3:1)0.75 uM+/-0.09Ach (6 uM)Yu,R. et al. (2018)
(mutant α9[N154G]α10 α9:α10 subunit ratio of 3:1)17.02 uM+/-3.17Ach (6 uM)Yu,R. et al. (2018)
(human a9 rat a10)975.4nM+/-3140.850uM AchYu,R. et al. (2013)
(α9:α10 subunit ratio of 1:3)1000 nM+/-100Ach (6 uM)Liang,J. et al. (2020)
(mutant α9α10[G154N] α9:α10 subunit ratio of 1:3)0.75 uM+/-0.05Ach (6 uM)Yu,R. et al. (2018)
R. norvegicus70.0nM+/-251.550uM AchYu,R. et al. (2013)
109nM10uM AchHalai,R. et al. (2009)
109nM30-100 mM AchSafavi-Hemami,H. et al. (2011)
19nM10uM AchVincler,M. et al. (2006)
64.2nM+/-151.130uM AchNevin,S.T. et al. (2007)
28.3 nM[20.8-38.5]ACh(6 μM)Cai,F. et al. (2018)

Percentage inhibition: Nicotinic acetylcholine receptors

TargetOrganism% inhibitionConcentrationAgonistRef
α9α10H. sapiens42%1 μMACh(6 μM)Chu,X. et al. (2019)
Unknown65+/-5100nM30uM Ach 16 Klimis,H. et al. (2011)
89+/-51uM30uM AchKlimis,H. et al. (2011)

Synthetic variants
Vc1.1 [C2(Agl),C8(Agl)]G(Agl)CSDPR(Agl)NYDHPEIC(nh2)
Vc1.1 [C2H,C8F,insC_GGAAGG] cyclicGHCSDPRFNYDHPEICGGAAGG
Vc1.1 [C3(Agl),C16(Agl)]GC(Agl)SDPRCNYDHPEI(Agl)(nh2)
Vc1.1 [D11E,E14A,insC_GGAAGG] cyclicGCCSDPRCNYEHPAICGGAAGG
Vc1.1 [E14Gla]GCCSDPRCNYDHP(Gla)IC(nh2)
Vc1.1 [N9W,insC_GGAAGG] cyclicGCCSDPRCWYDHPEICGGAAGG
Vc1.1 [P6O]GCCSDORCNYDHPEIC(nh2)
Vc1.1 [insC_GGAAGG]GCCSDPRCNYDHPEICGGAAGG
Vc1.1 [insC_GGAAGG] cyclicGCCSDPRCNYDHPEICGGAAGG
Vc1.1 [insN_G,ins_GLPET] cyclicGGCCSDPRCNYDHPEICGLPET
Vc1.1 dimer GCCSDPRCNYDHPEICGRRRRGGCCSDPRCNYDHPEIC
Vc1.1[C2H,C8F]GHCSDPRFNYDHPEIC(nh2)
Vc1.1[D11(Gla)]GCCSDPRCNY(Gla)HPEIC(nh2)
Vc1.1[D11A]GCCSDPRCNYAHPEIC(nh2)
Vc1.1[D11E]GCCSDPRCNYEHPEIC(nh2)
Vc1.1[D11K]GCCSDPRCNYKHPEIC(nh2)
Vc1.1[D11N]GCCSDPRCNYNHPEIC(nh2)
Vc1.1[D5A]GCCSAPRCNYDHPEIC(nh2)
Vc1.1[D5K]GCCSKPRCNYDHPEIC(nh2)
Vc1.1[E14A]GCCSDPRCNYDHPAIC(nh2)
Vc1.1[E14D]GCCSDPRCNYDHPDIC(nh2)
Vc1.1[E14K]GCCSDPRCNYDHPKIC(nh2)
Vc1.1[G1A]ACCSDPRCNYDHPEIC(nh2)
Vc1.1[G1AcG,N9R](AcG)CCSDPRCRYDHPEIC(nh2)
Vc1.1[G1BzG,N9R](BzG)CCSDPRCRYDHPEIC(nh2)
Vc1.1[G1BzG](BzG)CCSDPRCNYDHPEIC(nh2)
Vc1.1[G1D]DCCSDPRCNYDHPEIC(nh2)
Vc1.1[G1K]KCCSDPRCNYDHPEIC(nh2)
Vc1.1[H12A]GCCSDPRCNYDAPEIC(nh2)
Vc1.1[H12D]GCCSDPRCNYDDPEIC(nh2)
Vc1.1[H12K]GCCSDPRCNYDKPEIC(nh2)
Vc1.1[I15A]GCCSDPRCNYDHPEAC(nh2)
Vc1.1[I15D]GCCSDPRCNYDHPEDC(nh2)
Vc1.1[I15K]GCCSDPRCNYDHPEKC(nh2)
Vc1.1[N9A]GCCSDPRCAYDHPEIC(nh2)
Vc1.1[N9D]GCCSDPRCDYDHPEIC(nh2)
Vc1.1[N9F]GCCSDPRCFYDHPEIC(nh2)
Vc1.1[N9G]GCCSDPRCGYDHPEIC(nh2)
Vc1.1[N9I]GCCSDPRCIYDHPEIC(nh2)
Vc1.1[N9K]GCCSDPRCKYDHPEIC(nh2)
Vc1.1[N9L]GCCSDPRCLYDHPEIC(nh2)
Vc1.1[N9R,D11N]GCCSDPRCRYNHPEIC(nh2)
Vc1.1[N9R,D11R]GCCSDPRCRYRHPEIC(nh2)
Vc1.1[N9R,D11S]GCCSDPRCRYSHPEIC(nh2)
Vc1.1[N9R]GCCSDPRCRYDHPEIC(nh2)
Vc1.1[N9S,Y10V,D11N,I15L]GCCSDPRCSVNHPELC(nh2)
Vc1.1[N9W]GCCSDPRCWYDHPEIC(nh2)
Vc1.1[P13A]GCCSDPRCNYDHAEIC(nh2)
Vc1.1[P13D]GCCSDPRCNYDHDEIC(nh2)
Vc1.1[P13K]GCCSDPRCNYDHKEIC(nh2)
Vc1.1[P6(Hyp)]GCCSDORCNYDHPEIC(nh2)
Vc1.1[P6A]GCCSDARCNYDHPEIC(nh2)
Vc1.1[P6D]GCCSDDRCNYDHPEIC(nh2)
Vc1.1[P6K]GCCSDKRCNYDHPEIC(nh2)
Vc1.1[R7A]GCCSDPACNYDHPEIC(nh2)
Vc1.1[R7D]GCCSDPDCNYDHPEIC(nh2)
Vc1.1[R7K]GCCSDPKCNYDHPEIC(nh2)
Vc1.1[S4(Dab),N9A]GCC(Dab)DPRCAYDHPEIC(nh2)
Vc1.1[S4(Dab),N9W]GCC(Dab)DPRCWYDHPEIC(nh2)
Vc1.1[S4(Dab)]GCC(Dab)DPRCNYDHPEIC(nh2)
Vc1.1[S4(Dap)]GCC(Dap)DPRCNYDHPEIC(nh2)
Vc1.1[S4A]GCCADPRCNYDHPEIC(nh2)
Vc1.1[S4D]GCCDDPRCNYDHPEIC(nh2)
Vc1.1[S4K,N9A]GCCKDPRCAYDHPEIC(nh2)
Vc1.1[S4K]GCCKDPRCNYDHPEIC(nh2)
Vc1.1[S4R]GCCRDPRCNYDHPEIC(nh2)
Vc1.1[Y10(F(4-Cl))]GCCSDPRCN(F(4-Cl))DHPEIC(nh2)
Vc1.1[Y10(F(4-F))]GCCSDPRCN(F(4-F))DHPEIC(nh2)
Vc1.1[Y10A]GCCSDPRCNADHPEIC(nh2)
Vc1.1[Y10D]GCCSDPRCNDDHPEIC(nh2)
Vc1.1[Y10F]GCCSDPRCNFDHPEIC(nh2)
Vc1.1[Y10K]GCCSDPRCNKDHPEIC(nh2)
Vc1.1[del 9-16, C3S]GCSSDPRC(nh2)
Vc1.1[del1G,N9R]CCSDPRCRYDHPEIC(nh2)
Vc1.1[insC_G(Nmv)G(Nmv)GV] cyclicGCCSDPRCNYDHPEICG(Nmv)G(Nmv)GV
Vc1.1[insC_GE(Nmg)E(Nmg)E] cyclicGCCSDPRCNYDHPEICGE(Nmg)E(Nmg)E
Vc1.1[insC_GK(Nmg)KGK] cyclicGCCSDPRCNYDHPEICGK(Nmg)KGK
hVc1.1GHCSDPRFNYDHPEICGGAAGG

References
Clark,R.J., Fischer,H., Nevin,S.T., Adams,D.J. and Craik,D.J. (2006) The synthesis, structural characterization, and receptor specificity of the alpha-conotoxin Vc1.1 J. Biol. Chem. 281:23254-23263
Sandall,D.W., Satkunanathan,N., Keays,D.A., Polidano,M.A., Liping,X., Pham,V., Down,J.G., Khalil,Z., Livett,B.G. and Gayler,K.R. (2003) A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo Biochemistry 42:6904-6911
Safavi-Hemami,H., Siero,W.A., Kuang,Z., Williamson,N.A., Karas,J.A., Page,L.R., MacMillan,D., Callaghan,B., Kompella,S.N., Adams,D.J., Norton,R.S., and Purcell,A.W. (2011) Embryonic toxin expression in the cone snail Conus victoriae: primed to kill or divergent function? J. Biol. Chem. 286:22546-22557
Halai,R., Clark,R.J., Nevin,S.T., Jensen,J.E., Adams,D.J. and Craik,D.J. (2009) Scanning mutagenesis of alpha-conotoxin Vc1.1 reveals residues crucial for activity at the alpha9alpha10 nicotinic acetylcholine receptor. J. Biol. Chem.
Vincler,M., Wittenauer,S., Parker,R., Ellison,M., Olivera,B.M. and McIntosh,J.M. (2006) Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors. Proc. Natl. Acad. Sci. U.S.A. 103:17880-17884
Cuny,H., Kompella,S.N., Tae,H.S., Yu,R. and Adams,D.J. (2016) Key Structural Determinants in the Agonist Binding Loops of Human β2 and β4 Nicotinic Acetylcholine Receptor Subunits Contribute to α3β4 Subtype Selectivity of α-Conotoxins. J. Biol. Chem. 291:23779-23792
Klimis,H., Adams,D.J., Callaghan,B., Nevin,S., Alewood,P.F., Vaughan,C.W., Mozar,C.A. and Christie,M.J. (2011) A novel mechanism of inhibition of high-voltage activated calcium channels by α-conotoxins contributes to relief of nerve injury-induced neuropathic pain. Pain 152:259-266
Nevin,S.T., Clark,R.J., Klimis,H., Christie,M.J., Craik,D.J. and Adams,D.J. (2007) Are alpha9alpha10 nicotinic acetylcholine receptors a pain target for alpha-conotoxins? Mol. Pharmacol. 72:1406-1410
Callaghan,B., Haythornthwaite,A., Berecki,G., Clark,R.J., Craik,D.J. and Adams,D.J. (2008) Analgesic alpha-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation. J. Neurosci. 28:10943-10951
Yu,R., Kompella,S.N., Adams,D.J., Craik,D.J. and Kaas,Q. (2013) Determination of the α-Conotoxin Vc1.1 Binding Site on the α9α10 Nicotinic Acetylcholine Receptor. J. Med. Chem.
Tabassum, N., Tae, H.S., Jia, X., Kaas, Q., Jiang, T., Adams, D.J. and Yu, R. (2017) Role of CysI-CysIII Disulfide Bond on the Structure and Activity of α-Conotoxins at Human Neuronal Nicotinic Acetylcholine Receptors ACS omega 2:4621-4631
Liang,J., Tae,H.S., Xu,X., Jiang,T., Adams,D.J. and Yu,R (2020) Dimerization of α-Conotoxins as a Strategy to Enhance the Inhibition of the Human α7 and α9α10 Nicotinic Acetylcholine Receptors J. Med. Chem 63:2974-2985
Chu,X., Tae,H.S., Xu,Q., Jiang,T., Adams,D.J. and Yu,R (2019) α-Conotoxin Vc1.1 Structure-Activity Relationship at the Human α9α10 Nicotinic Acetylcholine Receptor Investigated by Minimal Side Chain Replacement ACS Chem Neurosci 10:4328-4336
Yu,R., Tae,H.S., Tabassum,N., Shi,J., Jiang,T. and Adams,D.J. (2018) Molecular Determinants Conferring the Stoichiometric-Dependent Activity of α-Conotoxins at the Human α9α10 Nicotinic Acetylcholine Receptor Subtype J. Med. Chem. 61:4628-4634
Cai,F., Xu,N., Liu,Z., Ding,R., Yu,S., Dong,M., Wang,S., Shen,J., Tae,H.S., Adams,D.J., Zhang,X. and Dai,Q. (2018) Targeting of N-Type Calcium Channels via GABAB-Receptor Activation by α-Conotoxin Vc1.1 Variants Displaying Improved Analgesic Activity J. Med. Chem. 61:10198-10205

Internal links
Nucleic acids
Structure SOLUTION STRUCTURE OF ALPHA-CONOTOXIN VC1.1

External links
Ncbi 2H8S_A

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