SIIIA (P02707) Protein Card

General Information

Name	SIIIA
Alternative name(s)	S3-RDHAR04
Organism	Conus striatus (Striated cone)
Organism region	Indo-Pacific
Organism diet	piscivorous
Protein Type	Wild type
Protein precursor	SIIIA precursor (825) SIIIA precursor (4905)
Notes	The experimental evidence of the presence of this peptide in the venom come from Schroeder et al. 2008. Block tetrodotoxin resistant (TTX-R) and sensitive (TTX-S) Na channels (Bulaj et al 2005). Presumably interacts with site 1 in the Na channel pore, because SIIIA competes with TIIIA (Schroeder et al 2008), which in turn competes with saxitoxin (Lewis et al 2007). 10 μM rapidly blocks A-fiber compound action potentials in mouse sciatic nerve. Slowly blocks C-fiber CAPs [Wilson,M.J., Zhang,M (2015)].

Classification

Conopeptide class	conotoxin
Gene superfamily	M superfamily
Cysteine framework	III
Pharmacological family	mu conotoxin

Sequence

ZNCCNGGCSSKWCRDHARCC(nh2)
Modified residues	position symbol name 1 Z Pyroglutamic acid 21 nh2 C-term amidation
Sequence evidence	protein level
Average Mass	NA
Monoisotopic Mass	NA
Isoelectric Point	11.62
Extinction Coefficient [280nm]	5500.00

Activity

IC50: Voltage-Gated Sodium Channels

Target	Organism	IC50		Ref
Nav1.1	R. norvegicus	11.0uM	+/-1.2	Yao,S. et al. (2008)
Nav1.2	R. norvegicus	790nM		Schroeder,C.I. et al. (2008)
Nav1.3	R. norvegicus	5.3uM		Schroeder,C.I. et al. (2008)
		11.0uM	+/-1.4	Yao,S. et al. (2008)
Nav1.4	R. norvegicus	0.56uM	+/-0.29	Leipold,E. et al. (2011)
		330nM		Schroeder,C.I. et al. (2008)
		130nM	+/-15	Yao,S. et al. (2008)
Nav1.5	R. norvegicus	251uM	+/-38	Yao,S. et al. (2008)
Nav1.6	M. musculus	760nM	+/-60	Yao,S. et al. (2008)
Nav1.7	R. norvegicus	65uM	+/-6	Yao,S. et al. (2008)
Nav1.8	R. norvegicus	>10uM		Wilson,M.J. et al. (2011)

Kd: Voltage-Gated Sodium Channels

Target	Organism	Kd		Ref
Nav1.2	R. norvegicus	50nM	+/-17	Wilson,M.J. et al. (2011)

Ki: Voltage-Gated Sodium Channels

Target	Organism		Ki		Competitor	Agonist	Ref
Nav1.2	R. norvegicus		9.55 nM		125I-TIIIA		Schroeder,C.I. et al. (2008)
Nav1.4	R. norvegicus		21.38 nM		125I-TIIIA		Schroeder,C.I. et al. (2008)

Percentage inhibition: Voltage-Gated Potassium Channels

Target	Organism	% inhibition		Concentration	Ref
Kv1.1	R. norvegicus	27.3	+/-3.7	10 uM	Leipold,E. et al. (2017)
Kv1.2	R. norvegicus	4		10 uM	Leipold,E. et al. (2017)
Kv1.3	R. norvegicus	12		10 uM	Leipold,E. et al. (2017)
Kv1.4	R. norvegicus	12		10 uM	Leipold,E. et al. (2017)
Kv1.5	R. norvegicus	3		10 uM	Leipold,E. et al. (2017)
Kv1.6	R. norvegicus	54.0	+/-1.3	10 uM	Leipold,E. et al. (2017)
Kv2.1	R. norvegicus	2		10 uM	Leipold,E. et al. (2017)

Percentage inhibition: Voltage-Gated Sodium Channels

Target	Organism	% inhibition		Concentration	Ref
Nav1.2	R. norvegicus	95		3uM	Schroeder,C.I. et al. (2008)
		95		10 uM	Leipold,E. et al. (2017)
Nav1.3	R. norvegicus	45		3uM	Schroeder,C.I. et al. (2008)
Nav1.4	R. norvegicus	89	+/-2	100uM	Leipold,E. et al. (2011)
		85		10 uM	Leipold,E. et al. (2017)
Nav1.5	H. sapiens	12	+/-10	100uM	Leipold,E. et al. (2011)
		16	+/-2	10uM	Leipold,E. et al. (2011)
	R. norvegicus	20		10 uM	Leipold,E. et al. (2017)
		0		3uM	Schroeder,C.I. et al. (2008)
Nav1.7	R. norvegicus	70		10 uM	Leipold,E. et al. (2017)
		0		3uM	Schroeder,C.I. et al. (2008)
Nav1.8	R. norvegicus	0		3uM	Schroeder,C.I. et al. (2008)
Nav TTX-R	R. norvegicus	100		1uM	Wang,C.Z. et al. (2006)
	R. pipiens	91	+/-8	5uM	Zhang,M.M. et al. (2006)
Nav TTX-S	R. norvegicus	0		500nM	Wang,C.Z. et al. (2006)

Synthetic variants

SIIIA[C3U,C13U]	ZNUCNGGCSSKWURDHARCC(nh2)
SIIIA[C4U,C19U]	ZNCUNGGCSSKWCRDHARUC(nh2)
SIIIA[C8U,C20U]	ZNCCNGGUSSKWCRDHARCU(nh2)
SIIIA[del1,D15A,H16D]	NCCNGGCSSKWCRADARCC(nh2)
SIIIA[del1,D15A,H16R]	NCCNGGCSSKACRARARCC(nh2)
SIIIA[del1,D15A,H16Y]	NCCNGGCSSKWCRAYARCC(nh2)
SIIIA[del1,D15A,insC_AA]	NCCNGGCSSKWCRAHARCCAA(nh2)
SIIIA[del1,D15A,insC_AD]	NCCNGGCSSKWCRAHARCCAD(nh2)
SIIIA[del1,D15A,insC_AK]	NCCNGGCSSKWCRAHARCCAK(nh2)
SIIIA[del1,D15A,insC_A]	NCCNGGCSSKWCRAHARCCA(nh2)
SIIIA[del1,D15A,insC_D]	NCCNGGCSSKWCRAHARCCD(nh2)
SIIIA[del1,D15A,insC_K]	NCCNGGCSSKWCRAHARCCK(nh2)
SIIIA[del1,D15A]	NCCNGGCSSKWCRAHARCC(nh2)
SIIIA[del1,D15K]	NCCNGGCSSKWCRKHARCC(nh2)
SIIIA[del1,H16A]	NCCNGGCSSKWCRDAARCC(nh2)
SIIIA[del1,K11A,R14A,D15A,H16D,R18A]	NCCNGGCSSAWCAADAACC(nh2)
SIIIA[del1,K11A,R14A,D15A,H16Y,R18A]	NCCNGGCSSAWCAAYAACC(nh2)
SIIIA[del1,K11A,R14A,D15A,R18A]	NCCNGGCSSAWCAAHAACC(nh2)
SIIIA[del1,K11A]	NCCNGGCSSAWCRDHARCC(nh2)
SIIIA[del1,K11R,W12A,D15A]	NCCNGGCSSRACRAHARCC(nh2)
SIIIA[del1,K11R,W12A]	NCCNGGCSSRACRDHARCC(nh2)
SIIIA[del1,R14A]	NCCNGGCSSKWCADHARCC(nh2)
SIIIA[del1,R18A]	NCCNGGCSSKWCRDHAACC(nh2)
SIIIA[del1,W12A]	NCCNGGCSSKACRDHARCC(nh2)
SIIIA[del1]	NCCNGGCSSKWCRDHARCC(nh2)

References

Wang,C.Z., Zhang,H., Jiang,H., Lu,W., Zhao,Z.Q. and Chi,C.W. (2006) A novel conotoxin from Conus striatus, mu-SIIIA, selectively blocking rat tetrodotoxin-resistant sodium channels Toxicon 47:122-132

Bulaj,G., West,P.J., Garrett,J.E., Watkins,M., Zhang,M.M., Norton,R.S., Smith,B.J., Yoshikami,D. and Olivera,B.M. (2005) Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels Biochemistry 44:7259-7265

Schroeder,C.I., Ekberg,J., Nielsen,K.J., Adams,D., Loughnan,M.L., Thomas,L., Adams,D.J., Alewood,P.F. and Lewis,R.J. (2008) Neuronally mu-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels. J. Biol. Chem. 283:21621-21628

Yao,S., Zhang,M.M., Yoshikami,D., Azam,L., Olivera,B.M., Bulaj,G. and Norton,R.S. (2008) Structure, dynamics, and selectivity of the sodium channel blocker mu-conotoxin SIIIA. Biochemistry 47:10940-10949

Leipold,E., Markgraf,R., Miloslavina,A., Kijas,M., Schirmeyer,J. , Imhof,D., and Heinemann,S.H (2011) Molecular determinants for the subtype specificity of μ-conotoxin SIIIA targeting neuronal voltage-gated sodium channels. Neuropharmacology 61:105-111

Schroeder,C.I., Adams,D., Thomas,L., Alewood,P.F. and Lewis,R.J. (2012) N- and C-terminal extensions of μ-conotoxins increase potency and selectivity for neuronal sodium channels. Biopolymers 98:161-165

Wilson,M.J., Zhang,M.M., Gajewiak,J., Azam,L., Rivier,J.E., Olivera,B.M. and Yoshikami,D. (2015) α- and β-subunit composition of voltage-gated sodium channels investigated with μ-conotoxins and the recently discovered μO§-conotoxin GVIIJ. J Neurophysiol 113:2289-2301

Leipold,E., Ullrich,F., Thiele,M., Tietze,A.A., Terlau,H., Imhof,D. and Heinemann,S.H. (2017) Subtype-specific block of voltage-gated K+ channels by μ-conopeptides Biochem. Biophys. Res. Commun. 482:1135-1140

Paul George,A.A., Heimer,P., Maaß,A., Hamaekers,J., Hofmann-Apitius,M., Biswas,A. and Imhof,D. (2018) Insights into the Folding of Disulfide-Rich μ-Conotoxins ACS Omega 3:12330-12340

Internal links

Protein Precursor	SIIIA precursor (825) SIIIA precursor (4905)
Nucleic acids
Structure	Structure, dynamics and selectivity of the sodium channel blocker mu-conotoxin SIIIA NMR solution structure of mu-conotoxin SIIIA

External links

Ncbi	AAO48588, Q86DU6

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 28 November 2023