PIIIA (P02228) Protein Card

General Information
Alternative name(s) P3.7,P3a
Organism Conus purpurascens
Organism region Eastern Pacific
Organism diet piscivorous
Protein Type Wild type
Protein precursor PIIIA precursor (1407)
Notes Bind to site 1 in the Na channel pore based on competitive binding assay using saxitoxin (Shon et al 1998). 10 μM rapidly blocks A-fiber but not C-fiber compound action potentials in mouse sciatic nerve [Wilson,M.J., Zhang,M (2015)].

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

Modified residues
1ZPyroglutamic acid
23nh2C-term amidation
Sequence evidence nucleic acid level
Average Mass NA
Monoisotopic Mass NA
Isoelectric Point 12.99
Extinction Coefficient [280nm] NA


IC50: Voltage-Gated Sodium Channels

Nav1.1R. norvegicus120nM+/-13Wilson,M.J. et al. (2011)
Nav1.2R. norvegicus690nMSafo,P. et al. (2000)
620nM+/-70Wilson,M.J. et al. (2011)
Nav1.3R. norvegicus3.2uM+/-0.8Wilson,M.J. et al. (2011)
Nav1.4R. norvegicus(PIIIA-3 (connectivity 1-2 3-4 5-6))203.7nM+/-25.7Tietze,A.A. et al. (2012)
(PIIIA-1 (connectivity 1-5 2-6 3-4))46.7nM+/-6.5Tietze,A.A. et al. (2012)
(PIIIA-2 (connectivity 1-4 2-5 3-6))103.2nM+/-9.9Tietze,A.A. et al. (2012)
36nM+/-8Wilson,M.J. et al. (2011)
41nMSafo,P. et al. (2000)
Nav1.5R. norvegicus>10uMWilson,M.J. et al. (2011)
Nav1.6M. musculus100nM+/-20Wilson,M.J. et al. (2011)
Nav1.7H. sapiens3.1uMSafo,P. et al. (2000)
R. norvegicus6.2uMSafo,P. et al. (2000)
>10uMWilson,M.J. et al. (2011)
Nav1.8R. norvegicus>10uMWilson,M.J. et al. (2011)
NavBhB. halodurans5 pM+/-10.81Finol-Urdaneta et al. (2019)

Kd: Voltage-Gated Sodium Channels

Nav1.1R. norvegicus53nM+/-4Zhang,M.M. et al. (2013)
(+NaVβ1)14nM+/-2Zhang,M.M. et al. (2013)
(+NaVβ3)17nM+/-3Zhang,M.M. et al. (2013)
(+NaVβ4)370nM+/-110Zhang,M.M. et al. (2013)
(+NaVβ2)140nM+/-20Zhang,M.M. et al. (2013)
Nav1.2R. norvegicus(+NaVβ3)220nM+/-20Zhang,M.M. et al. (2013)
(+NaVβ2)650nM+/-50Zhang,M.M. et al. (2013)
(+NaVβ4)1.10uM+/-0.05Zhang,M.M. et al. (2013)
620nM+/-40Zhang,M.M. et al. (2013)
(+NaVβ1)240nM+/-30Zhang,M.M. et al. (2013)
Nav1.6R. norvegicus(+NaVβ2)243nM+/-58Zhang,M.M. et al. (2013)
81nM+/-32Zhang,M.M. et al. (2013)
(+NaVβ4)951nM+/-151Zhang,M.M. et al. (2013)
(+NaVβ1)5nM+/-1Zhang,M.M. et al. (2013)
(+NaVβ3)9nM+/-2Zhang,M.M. et al. (2013)

Percentage inhibition: Voltage-Gated Potassium Channels

TargetOrganism% inhibitionConcentrationRef
Kv1.1R. norvegicus73.0+/-5.110 uMLeipold,E. et al. (2017)
Kv1.2R. norvegicus010 uMLeipold,E. et al. (2017)
Kv1.3R. norvegicus1510 uMLeipold,E. et al. (2017)
Kv1.4R. norvegicus410 uMLeipold,E. et al. (2017)
Kv1.5R. norvegicus010 uMLeipold,E. et al. (2017)
Kv1.6R. norvegicus80.3+/-2.910 uMLeipold,E. et al. (2017)
Kv2.1R. norvegicus310 uMLeipold,E. et al. (2017)

Percentage inhibition: Voltage-Gated Sodium Channels

TargetOrganism% inhibitionConcentrationRef
Nav1.2R. norvegicus7510 uMLeipold,E. et al. (2017)
Nav1.4R. norvegicus9810 uMLeipold,E. et al. (2017)
Nav1.5R. norvegicus1510 uMLeipold,E. et al. (2017)
Nav1.7R. norvegicus4510 uMLeipold,E. et al. (2017)
Nav TTX-RR. pipiens8+/-105uMZhang,M.M. et al. (2006)

Synthetic variants

Shon,K.-J., Olivera,B.M., Watkins,M., Jacobsen,R.B., Gray,W.R., Floresca,C.Z., Cruz,L.J., Hillyard,D.R., Brink,A., Terlau,H. and Yoshikami,D. (1998) mu-Conotoxin PIIIA, a new peptide for discriminating among tetrodotoxin-sensitive Na channel subtypes J. Neurosci. 18:4473-4481
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
Nielsen,K.J., Watson,M., Adams,D.J., Hammarstroem,A.K., Gage,P.W., Hill,J.M., Craik,D.J., Thomas,L., Adams,D., Alewood,P.F. and Lewis,R.J. (2002) Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels J. Biol. Chem. 277:27247-27255
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
Zhang,M.M., Wilson,M.J., Azam,L., Gajewiak,J., Rivier,J.E., Bulaj,G., Olivera,B.M. and Yoshikami,D. (2013) Co-expression of Na(V)β subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking μ-conotoxins. Br. J. Pharmacol. 168:1597-1610
Tietze,A.A., Tietze,D., Ohlenschläger,O., Leipold,E., Ullrich,F., Kühl,T., Mischo,A., Buntkowsky,G., Görlach,M., Heinemann,S.H. and Imhof,D. (2012) Structurally diverse μ-conotoxin PIIIA isomers block sodium channel NaV 1.4. Angew. Chem. Int. Ed. Engl. 51:4058-4061
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
Finol-Urdaneta, R.K., McArthur, J.R., Korkosh, V.S., Huang, S., McMaster, D., Glavica, R., Tikhonov, D.B., Zhorov, B.S. and French, R.J. (2019) Extremely Potent Block of Bacterial Voltage-Gated Sodium Channels by μ-Conotoxin PIIIA Marine drugs 17:510-527
Himaya, S.W.A., Mari, F. and Lewis, R.J. (2018) Accelerated proteomic visualization of individual predatory venoms of Conus purpurascens reveals separately evolved predation-evoked venom cabals Scientific reports 8:1-8
Heimer, P., Tietze, A.A., Bäuml, C.A., Resemann, A., Mayer, F.J., Suckau, D., Ohlenschläger, O., Tietze, D. and Imhof, D. (2018) Conformational μ-conotoxin PIIIA isomers revisited: Impact of cysteine pairing on disulfide-bond assignment and structure elucidation Analytical chemistry 90:3321-3327
Chen, F., Huang, W., Jiang, T. and Yu, R. (2018) Determination of the μ-Conotoxin PIIIA Specificity Against Voltage-Gated Sodium Channels from Binding Energy Calculations Marine drugs 16:153
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
Heimer,P., Schmitz,T., Bäuml,C.A. and Imhof,D. (2018) Synthesis and Structure Determination of μ-Conotoxin PIIIA Isomers with Different Disulfide Connectivities. J Vis Exp
Schmitz,T., Pengelley,S., Belau,E. and Imhof,D. (2020) LC-Trapped Ion Mobility Spectrometry-TOF MS Differentiation of 2- and 3-Disulfide-Bonded Isomers of the µ-Conotoxin PIIIA. Anal Chem 92:10920-10924

Internal links
Protein Precursor PIIIA precursor (1407)
Nucleic acids
NMR solution structure of PIIIA connectivity 1-5 2-6 3-4
NMR solution structure of PIIIA connectivity 1-4 2-5 3-6
NMR solution structure of PIIIA connectivity 1-2 3-4 5-6

External links
Ncbi 1R9I_A