RgIA (P02585) Protein Card

General Information
Name RgIA
Alternative name(s) Rg1a
Organism Conus regius
Organism region Eastern Pacific
Organism diet vermivorous
Protein Type Wild type
Protein precursor RgIA precursor (593)
Notes

This protein sequence has been predicted from the protein prosequence (Ellison et al. 2006). The final arginine is usually cleaved by an enzyme (CPE). The sequence Reg1e, a protein directly purified from the venom duct, seems to be the real mature peptide corresponding to the precursor sequence (it presents an hydroxyproline, a N-terminal amidation and does not have the arginine).

Rg1A (100 nm) significantly inhibited HVA Ca2+ channel currents in rat DRG neurons to 60.6 ± 4.5% of control (Callaghan et al. 2008).

Inhibition of N-type Ca2+ channel current through the GABAB in a9 KO mouse DRG neurons with an IC50 of 22.4 nM (Callaghan et al., 2010). The specific receptor remains unclear.

Inhibited HVA Ca2+ channel current via GABAB receptors in rat DRG neurons with an IC50 of 14.7 nM. (Halai 2011)

Alsharari et al.,2020 reported that RgIA reverses colitis signs in murine dextran sodium sulfate model.

RgIA promotes the proliferation of glioma C6 cells (Terpinskaya et al., 2021.


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

Sequence
GCCSDPRCRYRCR
Sequence evidence nucleic acid level
Average Mass 1570.79
Monoisotopic Mass 1569.62
Isoelectric Point 12.50
Extinction Coefficient [280nm] 1490.00

Activity

IC50: Nicotinic acetylcholine receptors

TargetOrganismIC50nhillAgonistRef
α1β1δεH. sapiens16uM10uM AchVincler,M. et al. (2006)
α2β2R. norvegicus>10uM100 uM AchEllison,M. et al. (2006)
α2β4R. norvegicus>10uM100 uM AchEllison,M. et al. (2006)
α3β2R. norvegicus>10uM100 uM AchEllison,M. et al. (2006)
α3β4R. norvegicus>10uM100 uM AchEllison,M. et al. (2006)
α4β2R. norvegicus>10uM100 uM AchEllison,M. et al. (2006)
α4β4R. norvegicus>10uM100 uM AchEllison,M. et al. (2006)
α6/α3β2β3R. norvegicus>10uM100 uM AchEllison,M. et al. (2006)
α6/α3β4R. norvegicus>10uM100 uM AchVincler,M. et al. (2006)
α7R. norvegicus3.31uM0.9200uM AchEllison,M. et al. (2008)
4.66uM1.2200 uM AchEllison,M. et al. (2006)
α9α10H. sapiens1400nM[1000-1960]0.51Ren et al. (2019)
510 nM[303-856]100 uM AchHuynh,P.N. et al. (2020)
510 nM[303-856]100 uM AchZheng N et al. (2021)
>10000 nM10 uM AChRomero,H.K. et al. (2017)
R. norvegicus(minus BAPTA)3.60nM0.9810uM AchEllison,M. et al. (2006)
(plus BAPTA)5.19nM1.210uM AchEllison,M. et al. (2006)
5.2nM10uM AchVincler,M. et al. (2006)
2.4 nM+/-0.70.6710 uM AChRomero,H.K. et al. (2017)
2.6nM[2.1-3.22]0.8Ren et al. (2019)
4.55nM1.110uM AchEllison,M. et al. (2006)
8.47nM1.350uM AchEllison,M. et al. (2008)
1.8 nM[1.4-2.2]100 uM AchHuynh,P.N. et al. (2020)
unidentified(nAChR was hybrid human ?9/rat ?10)40 nM[28-59]50 nMHalai,R. et al. (2011)

Percentage inhibition: Nicotinic acetylcholine receptors

TargetOrganism% inhibitionConcentrationRef
α9α10H. sapiens10+/-2.510 nMHuynh,P.N. et al. (2020)
unidentified(nAChR was hybrid human ?9/rat ?10. )60+/-450 nMHalai,R. et al. (2011)

Synthetic variants
Cy3-RgIA-5727(Cy3Trz)GC(Pen)TDPRCR(Ity)QC(β3hY)R
RgIA [C12c]GCCSDPRCRYRcR
RgIA [C2(Pen),S4T,R9(Cit),Y10(Ity),R11Q,R13Y]G(Pen)CTDPRC(Cit)(Ity)QCY
RgIA [C2(Smc),C3(Smc),S4T,R9(Cit),Y10(Ity),R11Q,R13Y]G(Smc)(Smc)TDPRC(Cit)(Ity)QCY
RgIA [C2(Smc),S4T,C8,R9(Cit),Y10(Ity),R11Q,R13Y]G(Smc)CTDPRC(Cit)(Ity)QCY
RgIA [C2c]GcCSDPRCRYRCR
RgIA [C3(Pen),S4T,R9(Cit),Y10(Ity),R11Q,C12(Pen),R13Y]GC(Pen)TDPRC(Cit)(Ity)Q(Pen)Y
RgIA [C3(Pen),S4T,R9(Cit),Y10(Ity),R11Q,R13Y]GC(Pen)TDPRC(Cit)(Ity)QCY
RgIA [C3(Pen),S4T,Y10(Ity),R11Q,R13(β3hY),insC_(Cit)]GC(Pen)TDPRCR(Ity)QC(β3hY)(Cit)
RgIA [C3(Pen),S4T,Y10(Ity),R11Q,R13(β3hY),insC_(Orn)]GC(Pen)TDPRCR(Ity)QC(β3hY)(Orn)
RgIA [C3(Pen),S4T,Y10(Ity),R11Q,R13(β3hY),insC_E]GC(Pen)TDPRCR(Ity)QC(β3hY)E
RgIA [C3(Pen),S4T,Y10(Ity),R11Q,R13(β3hY),insC_K]GC(Pen)TDPRCR(Ity)QC(β3hY)K
RgIA [C3(Pen),S4T,Y10(Ity),R11Q,R13(β3hY),insC_R]GC(Pen)TDPRCR(Ity)QC(β3hY)R
RgIA [C3(Pen),S4T,Y10(Ity),R11Q,R13(β3hY),insC_r]GC(Pen)TDPRCR(Ity)QC(β3hY)r
RgIA [C3(Pen),S4T,Y10(Ity),R11Q,R13Y,insC_R]GC(Pen)TDPRCR(Ity)QCYR
RgIA [C3(Pen),S4T,Y10(Ity),R11Q,R13Y]GC(Pen)TDPRCR(Ity)QCY
RgIA [C3(Pen),S4T,Y10(Ity),R11Q,R13y,insC_r]GC(Pen)TDPRCR(Ity)QCyr
RgIA [C3(Smc),S4T,R9(Cit),Y10(Ity),R11Q,R13Y]GC(Smc)TDPRC(Cit)(Ity)QCY
RgIA [C3(Smc),S4T,Y10(Ity),R11Q,ins13(bA)]GC(Smc)TDPRCR(Ity)QC(bA)R
RgIA [C3(Smc),S4T,Y10(Ity),R11Q,ins13(bhY)]GC(Smc)TDPRCR(Ity)QC(bhY)R
RgIA [C3c]GCcSDPRCRYRCR
RgIA [C8c]GCCSDPRcRYRCR
RgIA [Cys2Agl,Cys8Agl]G(Agl)CSDPR(Agl)RYRCR
RgIA [Cys3Agl,Cys12Agl]GC(Agl)SDPRCRYR(Agl)R
RgIA [D5E]GCCSEPRCRYRCR
RgIA [D5d]GCCSdPRCRYRCR
RgIA [G1a]aCCSDPRCRYRCR
RgIA [P6V]GCCSDVRCRYRCR
RgIA [P6p]GCCSDpRCRYRCR
RgIA [R11Cit]GCCSDPRCRY(Cit)CR
RgIA [R11K]GCCSDPRCRYKCR
RgIA [R11Nar]GCCSDPRCRY(Nar)CR
RgIA [R11Q]GCCSDPRCRYQCR
RgIA [R11hArg]GCCSDPRCRY(hArg)CR
RgIA [R11r]GCCSDPRCRYrCR
RgIA [R13COOH-Phe] amidatedGCCSDPRCRYRC(COOH-Phe)(nh2)
RgIA [R13Cit]GCCSDPRCRYRC(Cit)
RgIA [R13F]GCCSDPRCRYRCF
RgIA [R13F] amidatedGCCSDPRCRYRCF(nh2)
RgIA [R13K]GCCSDPRCRYRCK
RgIA [R13W]GCCSDPRCRYRCW
RgIA [R13Y]GCCSDPRCRYRCY
RgIA [R13Y] amidatedGCCSDPRCRYRCR(nh2)
RgIA [R13r]GCCSDPRCRYRCr
RgIA [R7Cit]GCCSDP(Cit)CRYRCR
RgIA [R7K]GCCSDPKCRYRCR
RgIA [R7Nar]GCCSDP(Nar)CRYRCR
RgIA [R7hArg]GCCSDP(hArg)CRYRCR
RgIA [R7r,R9r,R11r,R13r]GCCSDPrCrYrCr
RgIA [R7r,R9r,R11r,del13] amidatedGCCSDPrCrYrC(nh2)
RgIA [R7r]GCCSDPrCRYRCR
RgIA [R9A]GCCSDPRCAYRCR
RgIA [R9Cit]GCCSDPRC(Cit)YRCR
RgIA [R9K]GCCSDPRCKYRCR
RgIA [R9Nar]GCCSDPRC(Nar)YRCR
RgIA [R9hArg]GCCSDPRC(hArg)YRCR
RgIA [R9r]GCCSDPRCrYRCR
RgIA [S4A]GCCADPRCRYRCR
RgIA [S4T,C2(Pen),C8(Pen),R9(Cit),Y10(Ity),R11Q,R13Y]G(Pen)CTDPR(Pen)(Cit)(Ity)QCY
RgIA [S4T,C8(Pen),R9(Cit),Y10(Ity),R11Q,R13Y]GCCTDPR(Pen)(Cit)(Ity)QCY
RgIA [S4T,R9(Cit),Y10(Ity),R11Q,C12(Pen),R13Y]GCCTDPRC(Cit)(Ity)Q(Pen)Y
RgIA [S4T,R9(Cit),Y10(Ity),R11Q,R13Y]GCCTDPRC(Cit)(Ity)QCY
RgIA [S4T,Y10(Ity),R11Q,R13Y]GCCTDPRCR(Ity)QCY
RgIA [S4s]GCCsDPRCRYRCR
RgIA [Y10Iyr]GCCSDPRCR(Ity)RCR
RgIA [Y10W]GCCSDPRCRWRCR
RgIA [Y10y]GCCSDPRCRyRCR
RgIA [del13,insC_GAAGG] cyclicGCCSDPRCRYRCGAAGG
RgIA [del13,insC_GAAG] cyclicGCCSDPRCRYRCGAAG
RgIA [del13,insC_GAA] cyclicGCCSDPRCRYRCGAA
RgIA [del13,insC_GGAAGAG] cyclicGCCSDPRCRYRCGGAAGAG
RgIA [del13,insC_GGAAGG] cyclicGCCSDPRCRYRCGGAAGG
RgIA [del13]GCCSDPRCRYRC(nh2)
RgIA[R9(Cit),Y10(Ity)]GCCSDPRC(Cit)(Ity)RCR
RgIA[S4T,R9(Cit),Y10(Ity),R11Q,insC_RR]GCCTDPRC(Cit)(Ity)QCRRR
RgIA[S4T,R9(Cit),Y10(Ity),R11Q]GCCTDPRC(Cit)(Ity)QCR
RgIA[Y10(Ity)]GCCSDPRCR(Ity)RCR

References
Ellison,M., Haberlandt,C., Gomez-Casati,M.E., Watkins,M., Elgoyhen,A.B., McIntosh,J.M. and Olivera,B.M. (2006) Alpha-RgIA: a novel conotoxin that specifically and potently blocks the alpha9alpha10 nAChR Biochemistry 45:1511-1517
Ellison,M., Feng,Z.P., Park,A.J., Zhang,X., Olivera,B.M., McIntosh,J.M. and Norton,R.S. (2008) Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues. J. Mol. Biol. 377:1216-1227
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
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
Halai,R., Callaghan,B., Daly,N.L., Clark,R.J., Adams,D.J. and Craik,D.J. (2011) Effects of cyclization on stability, structure, and activity of α-conotoxin RgIA at the α9α10 nicotinic acetylcholine receptor and GABA(B) receptor. J. Med. Chem. 54:6984-6992
Ren, J., Zhu, X., Xu, P., Li, R., Fu, Y., Dong, S., Zhangsun, D., Wu, Y. and Luo, S. (2019) d-Amino Acid Substitution of α-Conotoxin RgIA Identifies its Critical Residues and Improves the Enzymatic Stability Marine drugs 17:142
AlSharari,S.D., Toma,W., Mahmood,H.M., Michael McIntosh,J. and Imad Damaj,M. (2020) The α9α10 nicotinic acetylcholine receptors antagonist α-conotoxin RgIA reverses colitis signs in murine dextran sodium sulfate model Eur. J. Pharmacol. 173320
Huynh,P.N., Harvey,P.J., Gajewiak,J., Craik,D.J. and Michael McIntosh,J. (2020) Critical residue properties for potency and selectivity of α-Conotoxin RgIA towards α9α10 nicotinic acetylcholine receptors. Biochem. Pharmacol. :114124
Callaghan,B. and Adams,D.J. (2010) Analgesic α-conotoxins Vc1.1 and RgIA inhibit N-type calcium channels in sensory neurons of α9 nicotinic receptor knockout mice. Channels (Austin) 4:51-54
Terpinskaya,T.I., Osipov,A.V., Kryukova,E.V., Kudryavtsev,D.S., Kopylova,N.V., Yanchanka,T.L., Palukoshka,A.F., Gondarenko,E.A., Zhmak,M.N., Tsetlin,V.I. and Utkin,Y.N. (2021) α-Conotoxins and α-Cobratoxin Promote, while Lipoxygenase and Cyclooxygenase Inhibitors Suppress the Proliferation of Glioma C6 Cells. Mar Drugs 19
Romero,H.K., Christensen,S.B., Di Cesare Mannelli,L., Gajewiak,J., Ramachandra,R., Elmslie,K.S., Vetter,D.E., Ghelardini,C., Iadonato,S.P., Mercado,J.L., Olivera,B.M. and McIntosh,J.M. (2017) Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain. Proc Natl Acad Sci U S A 114
Zheng N, Christensen SB, Dowell C, Purushottam L, Skalicky JJ, McIntosh JM, Chou DH. (2021) Discovery of Methylene Thioacetal-Incorporated α-RgIA Analogues as Potent and Stable Antagonists of the Human α9β10 Nicotinic Acetylcholine Receptor for the Treatment of Neuropathic Pain J Med Chem 64:9513-9524
Pan S, Fan Y, Zhu X, Xue Y, Luo S, Wang X. (2021) From Crystal Structures of RgIA4 in Complex with Ac-AChBP to Molecular Determinants of Its High Potency of α9α10 nAChR. Mar Drugs 19:709

Internal links
Protein Precursor RgIA precursor (593)
Nucleic acids
Structure alpha-RgIA, a Novel Conotoxin That Blocks the alpha9alpha10 nAChR
Solution structure of RgIA
Co-crystal structure of Ac-AChBPP in complex with RgIA

External links
Ncbi ABB55879, P0C1D0

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