PIIIA (P02228) Protein Card

General Information
Name PIIIA
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)].

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

Sequence
ZRLCCGFOKSCRSRQCKOHRCC(nh2)
Modified residues
positionsymbolname
1ZPyroglutamic acid
8O4-Hydroxyproline
18O4-Hydroxyproline
23nh2C-term amidation
Sequence evidence nucleic acid level
Average Mass 2605.05
Monoisotopic Mass 2603.11
Isoelectric Point NA
Extinction Coefficient [280nm] NA

Activity

IC50: Voltage-Gated Sodium Channels

TargetOrganismIC50Ref
Nav1.1R. norvegicus120nM+/-13Wilson,M.J. et al. (2011)
Nav1.2R. norvegicus620nM+/-70Wilson,M.J. et al. (2011)
690nMSafo,P. et al. (2000)
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-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)
(PIIIA-1 (connectivity 1-5 2-6 3-4))46.7nM+/-6.5Tietze,A.A. et al. (2012)
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. norvegicus>10uMWilson,M.J. et al. (2011)
6.2uMSafo,P. et al. (2000)
Nav1.8R. norvegicus>10uMWilson,M.J. et al. (2011)

Kd: Voltage-Gated Sodium Channels

TargetOrganismKdRef
Nav1.1R. norvegicus(+NaVβ1)14nM+/-2Zhang,M.M. et al. (2013)
(+NaVβ2)140nM+/-20Zhang,M.M. et al. (2013)
53nM+/-4Zhang,M.M. et al. (2013)
(+NaVβ3)17nM+/-3Zhang,M.M. et al. (2013)
(+NaVβ4)370nM+/-110Zhang,M.M. et al. (2013)
Nav1.2R. norvegicus620nM+/-40Zhang,M.M. et al. (2013)
(+NaVβ3)220nM+/-20Zhang,M.M. et al. (2013)
(+NaVβ2)650nM+/-50Zhang,M.M. et al. (2013)
(+NaVβ1)240nM+/-30Zhang,M.M. et al. (2013)
(+NaVβ4)1.10uM+/-0.05Zhang,M.M. et al. (2013)
Nav1.6R. norvegicus(+NaVβ1)5nM+/-1Zhang,M.M. et al. (2013)
81nM+/-32Zhang,M.M. et al. (2013)
(+NaVβ4)951nM+/-151Zhang,M.M. et al. (2013)
(+NaVβ3)9nM+/-2Zhang,M.M. et al. (2013)
(+NaVβ2)243nM+/-58Zhang,M.M. et al. (2013)

Percentage inhibition: Voltage-Gated Sodium Channels

TargetOrganism% inhibitionConcentrationRef
Nav TTX-RR. pipiens8+/-105uMZhang,M.M. et al. (2006)

Synthetic variants
PIIIA [G6K]ZRLCCKFOKSCRSRQCKOHRCC(nh2)
PIIIA [K17A]ZRLCCAFOKSCRSRQCAOHRCC(nh2)
PIIIA [K17Q]ZRLCCAFOKSCRSRQCQOHRCC(nh2)
PIIIA [K17R]ZRLCCGFOKSCRSRQCROHRCC(nh2)
PIIIA [R12A]ZRLCCAFOKSCASRQCKOHRCC(nh2)
PIIIA [R12K]ZRLCCGFOKSCKSRQCKOHRCC(nh2)
PIIIA [R12Q]ZRLCCAFOKSCQSRQCKOHRCC(nh2)
PIIIA [R14A]ZRLCCGFOKSCRSAQCKOHRCC(nh2)
PIIIA [R14K]ZRLCCGFOKSCRSKQCKOHRCC(nh2)
PIIIA [R14Q]ZRLCCGFOKSCRSQQCKOHRCC(nh2)
PIIIA [R20A]ZRLCCAFOKSCRSRQCKOHACC(nh2)
PIIIA [R2A]ZALCCGFOKSCRSRQCKOHRCC(nh2)
PIIIA [S13D]ZRLCCAFOKSCRDRQCKOHRCC(nh2)

References
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

Internal links
Protein Precursor PIIIA precursor (1407)
Nucleic acids
Structure NMR SOLUTION STRUCTURE OF PIIIA TOXIN, NMR, 20 STRUCTURES
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

Tools