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., 2011). The specific targeted molecule remains unclear. Bony et al. (2022) demonstrated that 1 µM PeIA potentiated G protein coupled inwardly-rectifying potassium (GIRK)1/2 when co-expressed with human G protein-coupled GABAB receptors in HEK293T cells.

Classification

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

Sequence

GCCSHPACSVNHPELC(nh2)
Modified residues	position symbol name 17 nh2 C-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

Target	Organism		IC50		nhill	Agonist	Ref
α1β1γδ	M. musculus		>1uM			Ach	Daly,N.L. et al. (2011)
α3β2	R. norvegicus		97.5nM	+/-10.9	0.8	100uM Ach	Daly,N.L. et al. (2011)
			9.7nM	+/-2		100uM Ach	Hone,A.J. et al. (2012)
			23nM	+/-5	1.25	10uM ACh	McIntosh,J.M. et al. (2005)
			19.4 nM	[15.3-24.6]		Ach (100 uM)	Hone,A.J. et al. (2019)
			19.2 nM	+/-2.1		100 uM Ach	Hone,A.J. et al. (2013)
α3β4	R. norvegicus		480nM	+/-160	1.23	100uM ACh	McIntosh,J.M. et al. (2005)
			1.5uM	+/-0.2		100uM Ach	Hone,A.J. et al. (2012)
			1.57 μM	[1.28-1.92]		ACh(300 μM)	Hone,A.J. et al. (2020)
α4β2	R. norvegicus		>1uM			100uM Ach	Daly,N.L. et al. (2011)
			11.6uM	+/-3.6	3.02	10uM ACh	McIntosh,J.M. et al. (2005)
α6β4	R. norvegicus		262 nM	+/-70		100uM Ach	Hone,A.J. et al. (2013)
α6/α3β2β3	H. sapiens		16 nM	[14.2-18.1]		100 uM Ach	Hone et al. (2018)
	R. norvegicus		11.1nM	+/-3.9		100uM Ach	Hone,A.J. et al. (2012)
			16.3 nM	[13.2-20.2]		100 uM Ach	Hone et al. (2018)
			19.8 nM	[17.9-21.8]		Ach (100 uM)	Hone,A.J. et al. (2019)
			17.2 nM	+/-1.8		100uM Ach	Hone,A.J. et al. (2013)
α6/α3β4	H. sapiens		9.9 nM	[8.2-11.9]		300uM Ach	Hone et al. (2018)
			6.75 nM	[5.54-8.25]		300 uM ACh	Hone,A.J. et al. (2021)
	R. norvegicus		154 nM	[143-166]		300uM Ach	Hone et al. (2018)
			148nM	+/-28		100uM Ach	Hone,A.J. et al. (2012)
			130 nM	[117-145]		300 uM ACh	Hone,A.J. et al. (2021)
α7	H. sapiens		>1uM			200uM Ach	Daly,N.L. et al. (2011)
			>10000 nM			Ach (100 uM)	Liang,J. et al. (2020)
	R. norvegicus		1.8uM	+/-0.4	1.1	100uM ACh	McIntosh,J.M. et al. (2005)
α9α10	H. sapiens	(α9:α10 subunit ratio of 1:3)	21.9 nM	+/-1.3		Ach (6 uM)	Liang,J. et al. (2020)
	R. norvegicus		6.9nM	+/-2.6	0.88	10uM ACh	McIntosh,J.M. et al. (2005)
			33nM	+/-5		100uM Ach	Hone,A.J. et al. (2012)
			54.9nM	+/-9	0.6	30uM Ach	Daly,N.L. et al. (2011)

Synthetic variants

PeIA dimer	GCCSHPACSVNHPELCGRRRRGGCCSHPACSVNHPELC
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]PeIA	GCC(Hse)HPACSVNHPELC(nh2)
[S4I]PeIA	GCCIHPACSVNHPELC(nh2)
[S4L]PeIA	GCCLHPACSVNHPELC(nh2)
[S4T]PeIA	GCCTHPACSVNHPELC(nh2)
[S4V]PeIA	GCCVHPACSVNHPELC(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 J Neurochem

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

Bony,A.R., McArthur,J.R., Finol-Urdaneta,R.K., and Adams,D.J. (2022) Analgesic α-conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABAB receptors and reduce neuroexcitability. Br J Pharmacol 179:179-198

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

Please cite:
Kaas Q, Yu R, Jin AH, Dutertre S and Craik DJ. ConoServer: updated content, knowledge, and discovery tools in the conopeptide database. Nucleic Acids Research (2012) 40(Database issue):D325-30
Kaas Q, Westermann JC, Halai R, Wang CK and Craik DJ. ConoServer, a database for conopeptide sequences and structures. Bioinformatics (2008) 24(3):445-6

ConoServer is managed at the Institute of Molecular Bioscience IMB, Brisbane, Australia.

The database and computational tools found on this website may be used for academic research only, provided that it is referred to ConoServer, the database of conotoxins (http://www.conoserver.org) and the above reference is cited. For any other use please contact David Craik (d.craik@imb.uq.edu.au).

Contacts:
David Craik
Quentin Kaas

Last updated: Tuesday 21 March 2023