GIIIA (P01571) Protein Card

General Information

Name	GIIIA
Alternative name(s)	G3.9,GTx-I,Geographutoxin I,Myotoxin I
Organism	Conus geographus (Geography cone)
Organism region	Indo-Pacific
Organism diet	piscivorous
Protein Type	Wild type
Protein precursor	GIIIA precursor (1464)
Notes	Induce paralysis in vertebrates. Bind to tetrodotoxin sensitive Na channel (Cruz et al 1985) and, presumably, interact with site 1 in the Na channel pore. 10 μM rapidly blocks A-fiber but not C-fiber compound action potentials in mouse sciatic nerve [Wilson,M.J., Zhang,M (2015)].

Classification

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

Sequence

RDCCTOOKKCKDRQCKOQRCCA(nh2)
Modified residues	position symbol name 6 O 4-Hydroxyproline 7 O 4-Hydroxyproline 17 O 4-Hydroxyproline 23 nh2 C-term amidation
Sequence evidence	protein level
Average Mass	2609.04
Monoisotopic Mass	2607.12
Isoelectric Point	11.87
Extinction Coefficient [280nm]	NA

Activity

IC50: Voltage-Gated Sodium Channels

Target	Organism	IC50		nhill	Ref
Nav1.2	R. norvegicus	17.8uM	+/-1.7		Wilson,M.J. et al. (2011)
		2.7uM			Safo,P. et al. (2000)
Nav1.3	R. norvegicus	>10uM			Wilson,M.J. et al. (2011)
Nav1.4	R. norvegicus	0.069 μM	+/-0.005		Han et al. (2016)
		19nM	+/-2		Wilson,M.J. et al. (2011)
		19nM			Safo,P. et al. (2000)
Nav1.5	R. norvegicus	>10uM			Wilson,M.J. et al. (2011)
Nav1.6	M. musculus	680nM	+/-60		Wilson,M.J. et al. (2011)
Nav1.7	R. norvegicus	6.0uM			Safo,P. et al. (2000)
		>10uM			Wilson,M.J. et al. (2011)
Nav1.8	R. norvegicus	>10uM			Wilson,M.J. et al. (2011)

Kd: Voltage-Gated Sodium Channels

Target	Organism	Kd		Ref
Nav1.1	R. norvegicus	260nM	+/-90	Wilson,M.J. et al. (2011)

Percentage inhibition: Voltage-Gated Potassium Channels

Target	Organism	% inhibition		Concentration	Ref
Kv1.1	R. norvegicus	10		10 uM	Leipold,E. et al. (2017)
Kv1.2	R. norvegicus	0		10 uM	Leipold,E. et al. (2017)
Kv1.3	R. norvegicus	10		10 uM	Leipold,E. et al. (2017)
Kv1.4	R. norvegicus	2		10 uM	Leipold,E. et al. (2017)
Kv1.5	R. norvegicus	3		10 uM	Leipold,E. et al. (2017)
Kv1.6	R. norvegicus	10		10 uM	Leipold,E. et al. (2017)
Kv2.1	R. norvegicus	0		10 uM	Leipold,E. et al. (2017)

Percentage inhibition: Voltage-Gated Sodium Channels

Target	Organism	% inhibition		Concentration	Ref
Nav1.2	R. norvegicus	25		10 uM	Leipold,E. et al. (2017)
Nav1.4	R. norvegicus				Harvey,P.J. et al. (2018)
		99		10 uM	Leipold,E. et al. (2017)
Nav1.5	R. norvegicus	2		10 uM	Leipold,E. et al. (2017)
Nav1.7	R. norvegicus	20		10 uM	Leipold,E. et al. (2017)
Nav TTX-R	R. pipiens	0		5uM	Zhang,M.M. et al. (2006)

Synthetic variants

GIIIA [A10C, A21C]	RDCCTOOKKAKDRQCKOQRCAA(nh2)
GIIIA [A3C,A10C,A15C,A21C]	RDACTOOKKAKDRQAKOQRCAA(nh2)
GIIIA [A3C,A4C,A15C,A20C]	RDAATOOKKCKDRQAKOQRACA(nh2)
GIIIA [A3C]	RDACTOOKKCKDRQAKOQRCCA(nh2)
GIIIA [A4C,A10C,A20C,A21C]	RDCATOOKKAKDRQCKOQRAAA(nh2)
GIIIA [A4C,C20A]	RDCATOOKKCKDRQCKOQRACA(nh2)
GIIIA [R13A]	RDCCTOOKKCKDAQCKOQRCCA(nh2)

References

Safo,P., Rosenbaum,T., Shcherbatko,A., Choi,D.Y., Han,E., Toledo-Aral,J.J., Olivera,B.M., Brehm,P. and Mandel,G. (2000) Distinction among neuronal subtypes of voltage-activated sodium channels by mu-conotoxin PIIIA J. Neurosci. 20:76-80

Cruz,L.J., Gray,W.R., Olivera,B.M., Zeikus,R.D., Kerr,L., Yoshikami,D. and Moczydlowski,E. (1985) Conus geographus toxins that discriminate between neuronal and muscle sodium channels J. Biol. Chem. 260:9280-9288

Sato,S., Nakamura,H., Ohizumi,Y., Kobayashi,J. and Hirata,Y. (1983) The amino acid sequences of homologous hydroxyproline-containing myotoxins from the marine snail Conus geographus venom FEBS Lett. 155:277-280

Lancelin,J.M., Kohda,D., Tate,S., Yanagawa,Y., Abe,T., Satake,M. and Inagaki,F. (1991) Tertiary structure of conotoxin GIIIA in aqueous solution Biochemistry 30:6908-6916

Wakamatsu,K., Kohda,D., Hatanaka,H., Lancelin,J.M., Ishida,Y., Oya,M., Nakamura,H., Inagaki,F. and Sato,K. (1992) Structure-activity relationships of mu-conotoxin GIIIA: structure determination of active and inactive sodium channel blocker peptides by NMR and simulated annealing calculations Biochemistry 31:12577-12584

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

Wilson,M.J., Yoshikami,D., Azam,L., Gajewiak,J., Olivera,B.M., Bulaj,G. and Zhang,M.M. (2011) μ-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. Proc. Natl. Acad. Sci. U.S.A. 108:10302-10307

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

Han, P., Wang, K., Dai, X., Cao, Y., Liu, S., Jiang, H., Fan, C., Wu, W. and Chen, J. (2016) The Role of Individual Disulfide Bonds of μ-Conotoxin GIIIA in the Inhibition of Nav1. 4 Marine drugs 14:213

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

Harvey,P.J., Kurniawan,N.D., Finol-Urdaneta,R.K., McArthur,J.R., Van Lysebetten,D., Dash,T.S., Hill,J.M., Adams,D.J., Durek,T. and Craik,D.J. (2018) NMR Structure of μ-Conotoxin GIIIC: Leucine 18 Induces Local Repacking of the N-Terminus Resulting in Reduced NaV Channel Potency Molecules 23:2715

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	GIIIA precursor (1464)
Nucleic acids
Structure	STRUCTURE-ACTIVITY RELATIONSHIPS OF MU-CONOTOXIN GIIIA: STRUCTURE DETERMINATION OF ACTIVE AND INACTIVE SODIUM CHANNEL BLOCKER PEPTIDES BY NMR AND SIMULATED ANNEALING CALCULATIONS STRUCTURE-ACTIVITY RELATIONSHIPS OF MU-CONOTOXIN GIIIA: STRUCTURE DETERMINATION OF ACTIVE AND INACTIVE SODIUM CHANNEL BLOCKER PEPTIDES BY NMR AND SIMULATED ANNEALING CALCULATIONS Conotoxin GIIIA Conotoxin GIIIA

External links

Ncbi	1TCG_A, 1TCJ_A

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: Thursday 28 September 2023