PeIA (P02608) Protein Card

General Information
Name PeIA
Alternative name(s) Pe1a
Organism Conus pergrandis
Organism region Indo-Pacific
Protein Type Wild type
Protein precursor PeIA precursor (5)
Notes Inhibition of N-type Ca2+ channel current through the GABAB in rat DRG neurons with an IC50 of 1.1nM (Daly et al.). The specific targeted molecule remains unclear.

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

Sequence
GCCSHPACSVNHPELC(nh2)
Modified residues
positionsymbolname
17nh2C-term amidation
Sequence evidence nucleic acid level
Average Mass 1651.86
Monoisotopic Mass 1650.62
Isoelectric Point 6.81
Extinction Coefficient [280nm] NA

Activity

IC50: Nicotinic acetylcholine receptors

TargetOrganismIC50nhillAgonistRef
α1β1γδM. musculus>1uMAchDaly,N.L. et al. (2011)
α3β2R. norvegicus19.2 nM+/-2.1100 uM AchHone,A.J. et al. (2013)
19.4 nM[15.3-24.6]Ach (100 uM)Hone,A.J. et al. (2019)
9.7nM+/-2100uM AchHone,A.J. et al. (2012)
23nM+/-51.2510uM AChMcIntosh,J.M. et al. (2005)
97.5nM+/-10.90.8100uM AchDaly,N.L. et al. (2011)
α3β4R. norvegicus1.5uM+/-0.2100uM AchHone,A.J. et al. (2012)
480nM+/-1601.23100uM AChMcIntosh,J.M. et al. (2005)
1.57 μM[1.28-1.92]ACh(300 μM)Hone,A.J. et al. (2020)
α4β2R. norvegicus>1uM100uM AchDaly,N.L. et al. (2011)
11.6uM+/-3.63.0210uM AChMcIntosh,J.M. et al. (2005)
α6β4R. norvegicus262 nM+/-70100uM AchHone,A.J. et al. (2013)
α6/α3β2β3H. sapiens16 nM [14.2-18.1]100 uM AchHone et al. (2018)
R. norvegicus11.1nM+/-3.9100uM AchHone,A.J. et al. (2012)
19.8 nM[17.9-21.8]Ach (100 uM)Hone,A.J. et al. (2019)
16.3 nM[13.2-20.2]100 uM AchHone et al. (2018)
17.2 nM+/-1.8100uM AchHone,A.J. et al. (2013)
α6/α3β4H. sapiens9.9 nM[8.2-11.9]300uM AchHone et al. (2018)
6.75 nM[5.54-8.25]300 uM AChHone,A.J. et al. (2021)
R. norvegicus154 nM[143-166]300uM AchHone et al. (2018)
148nM+/-28100uM AchHone,A.J. et al. (2012)
130 nM[117-145]300 uM AChHone,A.J. et al. (2021)
α7H. sapiens>10000 nMAch (100 uM)Liang,J. et al. (2020)
>1uM200uM AchDaly,N.L. et al. (2011)
R. norvegicus1.8uM+/-0.41.1100uM AChMcIntosh,J.M. et al. (2005)
α9α10H. sapiens(α9:α10 subunit ratio of 1:3)21.9 nM+/-1.3Ach (6 uM)Liang,J. et al. (2020)
R. norvegicus33nM+/-5100uM AchHone,A.J. et al. (2012)
6.9nM+/-2.60.8810uM AChMcIntosh,J.M. et al. (2005)
54.9nM+/-90.630uM AchDaly,N.L. et al. (2011)

Synthetic variants
PeIA dimerGCCSHPACSVNHPELCGRRRRGGCCSHPACSVNHPELC
PeIA[A7V, S9H, N11R]GCCSHPVCHVRHPELC(nh2)
PeIA[A7V, S9N, N11R, L15I]GCCSHPVCNVRHPEIC(nh2)
PeIA[A7V, S9N, N11R]GCCSHPVCNVRHPELC(nh2)
PeIA[A7V, S9R, V10A, N11R, E14A]GCCSHPVCRARHPALC(nh2)
PeIA[A7V, S9R, V10A, N11R, P13R, E14A]GCCSHPVCRARHRALC(nh2)
PeIA[A7V,S9H,V10A,N11R,E14A]GCCSHPVCHARHPALC(nh2)
PeIA[A7V,S9H,V10A,N11R]GCCSHPVCHARHPELC(nh2)
PeIA[A7V]GCCSHPVCSVNHPELC(nh2)
PeIA[E14(Aad)]GCCSHPACSVNHP(Aad)LC(nh2)
PeIA[E14(Asu)]GCCSHPACSVNHP(Asu)LC(nh2)
PeIA[E14(Gla)]GCCSHPACSVNHP(Gla)LC(nh2)
PeIA[E14A]GCCSHPACSVNHPALC(nh2)
PeIA[E14D]GCCSHPACSVNHPDLC(nh2)
PeIA[E14N]GCCSHPACSVNHPNLC(nh2)
PeIA[E14Q]GCCSHPACSVNHPQLC(nh2)
PeIA[E14R]GCCSHPACSVNHPRLC(nh2)
PeIA[H12A]GCCSHPACSVNAPELC(nh2)
PeIA[H5A]GCCSAPACSVNHPELC(nh2)
PeIA[H5N]GCCSNPACSVNHPELC(nh2)
PeIA[L15(Nle)]GCCSHPACSVNHPE(Nle)C(nh2)
PeIA[L15A]GCCSHPACSVNHPEAC(nh2)
PeIA[L15I]GCCSHPACSVNHPEIC(nh2)
PeIA[L15R]GCCSHPACSVNHPERC(nh2)
PeIA[L15V]GCCSHPACSVNHPEVC(nh2)
PeIA[N11(Aad)]GCCSHPACSV(Aad)HPELC(nh2)
PeIA[N11(Api)]GCCSHPACSV(Api)HPELC(nh2)
PeIA[N11(Asu)]GCCSHPACSV(Asu)HPELC(nh2)
PeIA[N11A]GCCSHPACSVAHPELC(nh2)
PeIA[N11D]GCCSHPACSVDHPELC(nh2)
PeIA[N11E]GCCSHPACSVEHPELC(nh2)
PeIA[N11K]GCCSHPACSVKHPELC(nh2)
PeIA[N11R]GCCSHPACSVRHPELC(nh2)
PeIA[P13A]GCCSHPACSVNHAELC(nh2)
PeIA[P13O]GCCSHPACSVNHOELC(nh2)
PeIA[P13Q]GCCSHPACSVNHQELC(nh2)
PeIA[P13R]GCCSHPACSVNHRELC(nh2)
PeIA[P13S]GCCSHPACSVNHSELC(nh2)
PeIA[P6A]GCCSHAACSVNHPELC(nh2)
PeIA[P6O]GCCSHOACSVNHPELC(nh2)
PeIA[S4A]GCCAHPACSVNHPELC(nh2)
PeIA[S9A]GCCSHPACAVNHPELC(nh2)
PeIA[S9D]GCCSHPACDVNHPELC(nh2)
PeIA[S9H,V10(Nle),N11(Api),L15I]GCCSHPACH(Nle)(Api)HPEIC(nh2)
PeIA[S9H,V10(Nle),N11(Api)]GCCSHPACH(Nle)(Api)HPELC(nh2)
PeIA[S9H,V10A,N11R,E14A]GCCSHPACHARHPALC(nh2)
PeIA[S9H,V10A,N11R]GCCSHPACHARHPELC(nh2)
PeIA[S9H,V10I,N11(Api),L15(Nle)]GCCSHPACHI(Api)HPE(Nle)C(nh2)
PeIA[S9H,V10L,L15I]GCCSHPACHLNHPEIC(nh2)
PeIA[S9H,V10L,N11(Aad)]GCCSHPACHL(Aad)HPELC(nh2)
PeIA[S9H,V10L,N11(Api),L15I]GCCSHPACHL(Api)HPEIC(nh2)
PeIA[S9H,V10L,N11(Api)]GCCSHPACHL(Api)HPELC(nh2)
PeIA[S9H,V10L,N11(Asu)]GCCSHPACHL(Asu)HPELC(nh2)
PeIA[S9H,V10L,N11D]GCCSHPACHLDHPELC(nh2)
PeIA[S9H,V10L,N11E]GCCSHPACHLEHPELC(nh2)
PeIA[S9H,V10L]GCCSHPACHLNHPELC(nh2)
PeIA[S9H]GCCSHPACHVNHPELC(nh2)
PeIA[S9N]GCCSHPACNVNHPELC(nh2)
PeIA[S9R,V10I,N11(Api),L15(Nle)]GCCSHPACRI(Api)HPE(Nle)C(nh2)
PeIA[S9R]GCCSHPACRVNHPELC(nh2)
PeIA[S9T]GCCSHPACTVNHPELC(nh2)
PeIA[S9Y]GCCSHPACYVNHPELC(nh2)
PeIA[V10(Nle)]GCCSHPACS(Nle)NHPELC(nh2)
PeIA[V10A]GCCSHPACSANHPELC(nh2)
PeIA[V10D]GCCSHPACSDNHPELC(nh2)
PeIA[V10I]GCCSHPACSINHPELC(nh2)
PeIA[V10L]GCCSHPACSLNHPELC(nh2)
PeIA[V10R]GCCSHPACSRNHPELC(nh2)
PeIA[V10T]GCCSHPACSTNHPELC(nh2)
[S4Hse]PeIAGCC(Hse)HPACSVNHPELC(nh2)
[S4I]PeIAGCCIHPACSVNHPELC(nh2)
[S4L]PeIAGCCLHPACSVNHPELC(nh2)
[S4T]PeIAGCCTHPACSVNHPELC(nh2)
[S4V]PeIAGCCVHPACSVNHPELC(nh2)

References
McIntosh,J.M., Plazas,P.V., Watkins,M., Gomez-Casati,M.E., Olivera,B.M. and Elgoyhen,A.B. (2005) A novel alpha-conotoxin, PeIA, cloned from Conus pergrandis, discriminates between rat alpha9alpha10 and alpha7 nicotinic cholinergic receptors J. Biol. Chem. 280:30107-30112
Daly,N.L., Callaghan,B., Clark,R.J., Nevin,S.T., Adams,D.J. and Craik,D.J. (2011) Structure and activity of alpha-conotoxin PeIA at nicotinic acetylcholine receptor subtypes and GABA(B) receptor-coupled N-type calcium channels. J. Biol. Chem. 286:10233-10237
Hone,A.J., Scadden,M., Gajewiak,J., Christensen,S., Lindstrom,J. and McIntosh,J.M. (2012) α-Conotoxin PeIA[S9H,V10A,E14N] potently and selectively blocks α6β2β3 versus α6β4 nicotinic acetylcholine receptors. Mol. Pharmacol. 82:972-982
Hone,A.J., Ruiz,M., Scadden,M., Christensen,S., Gajewiak,J., Azam,L. and McIntosh,J.M. (2013) Positional scanning mutagenesis of α-conotoxin PeIA identifies critical residues that confer potency and selectivity for α6/α3β2β3 and α3β2 nicotinic acetylcholine receptors. J. Biol. Chem. 288:25428-25439
Hone, A.J., Talley, T.T., Bobango, J., Melo, C.H., Hararah, F., Gajewiak, J., Christensen, S., Harvey, P.J., Craik, D.J. and McIntosh, J.M. (2018) Molecular determinants of α-conotoxin potency for inhibition of human and rat α6β4 nicotinic acetylcholine receptors Journal of Biological Chemistry 293:17838-17852
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
Hone,A.J., Fisher,F., Christensen,S., Gajewiak,J., Larkin,D., Whiteaker,P. and McIntosh,J.M. (2019) PeIA-5466: A Novel Peptide Antagonist Containing Non-natural Amino Acids That Selectively Targets α3β2 Nicotinic Acetylcholine Receptors J. Med. Chem. 62:6262-6275
Hone,A.J., Rueda-Ruzafa,L., Gordon,T.J., Gajewiak,J., Christensen,S., Dyhring,T., Albillos,A. and McIntosh,J.M. (2020) Expression of α3β2β4 nicotinic acetylcholine receptors by rat adrenal chromaffin cells determined using novel conopeptide antagonists Journal of Neurochemistry
Hone,A.J., Kaas,Q., Kearns,I., Hararah,F., Gajewiak,J., Christensen,S., Craik,D.J. and McIntosh,J.M. (2021) Computational and Functional Mapping of Human and Rat α6β4 Nicotinic Acetylcholine Receptors Reveals Species-Specific Ligand-Binding Motifs. J Med Chem 64:1685-1700

Internal links
Protein Precursor PeIA precursor (5)
Nucleic acids
Structure NMR structure of PeIA
Crystal structure of acetylcholine binding protein (AChBP) from Aplysia Californica in complex with alpha-conotoxin PeIA

External links
Ncbi AAY57814, Q1L777

Tools