TIA (P01634) Protein Card

General Information
Name TIA
Alternative name(s) T1a,Tu052
Organism Conus tulipa (tulip cone)
Organism region Indo-Pacific
Organism diet piscivorous
Protein Type Wild type
Protein precursor TIA precursor (8074)
TIA precursor (8075)
Notes

Full inhibition of the noradrenergic component of rat vas deferens contraction at 10 uM. Inhibited prazosin binding to a1-adrenoreceptors with pIC50 of ~7.5. Alanine mutants N2A, W3A, R4A, L7A, I8A & R12A had reduced binding potency (see "synthetic variants"), whilst other Ala mutants exhibited comparable potency.(Sharpe et al., 2003)

Ragnarsson et al., 2013 reported that TIA binding was dominated by a salt bridge and cation-π between Arg-4-TIA and Asp-327 and Phe-330, respectively, and a T-stacking-π interaction between Trp-3-TIA and Phe-330.

Dutt et al., 2019 reported that TIA showed inhibition to zebrafish escape response (IC50 0.19 ± 0.62 μM).


Classification
Conopeptide class conotoxin
Gene superfamily A superfamily
Cysteine framework I
Pharmacological family rho conotoxin

Sequence
FNWRCCLIPACRRNHKKFC(nh2)
Modified residues
positionsymbolname
20nh2C-term amidation
Sequence evidence protein level
Average Mass 2390.89
Monoisotopic Mass 2389.14
Isoelectric Point 12.82
Extinction Coefficient [280nm] 5500.00

Activity

IC50: Adrenoceptors

TargetOrganismIC50AgonistRef
α1A-adrenoceptorH. sapiens18nMBE (20-800 pm)Chen,Z. et al. (2004)
M. auratus(S318A mutant)80.61 nM+/-7.94125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(G317A mutant)46.88 nM+/-1.98125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(D327A mutnat)109.53 nM+/-11.43125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(F330A mutant)289.72 nM+/-22.07125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(F320A mutant)51.67 nM+/-3.9125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(L319A mutant)34.93 nM+/-1.62125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(L108A mutant)32.11 nM+/-2.31125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(F334A mutant)55.72 nM+/-2.27125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(W307A mutant)ND125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(V329A mutant)23.57 nM+/-3.07125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(P326A mutant)20.64 nM+/-4.53125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(D191A mutant)36.39 nM+/-4.2125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(F202A mutant)55.76 nM+/-2.68125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(K185A mutant)31.45 nM+/-1.97125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(P201A mutant)24.21 nM+/-1.55125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(K193A mutant)25.18 nM+/-2.7125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(T198A mutant)17.71 nM+/-5.25125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(C118A mutant)45.59 nM+/-0.092 125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(S321A mutant)68.35 nM+/-6.23125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(P325A mutant)44.18 nM+/-3.86125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(K324A mutant)4.85 nM+/-1.14125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(L323A mutant)39.63 nM+/-2.53125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(F310A mutant)4.54 nM+/-0.15125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(T322A mutant)48.81 nM+/-6.31125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(WT)27.81 nM+/-1.05125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(Y110A mutant)3.18 nM+/-0.86125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(W111A mutant)10.54 nM +/-0.54125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(V112A mutant)37.55 nM+/-4.09125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(L113A mutant)26.87 nM+/-3.31125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(P180A mutant)18.10 nM+/-2.25125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(L181A mutant)30.20 nM+/-2.48125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(L182A mutant)33.37 nM+/-3.81125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(E200A mutant)23.51 nM+/-1.32125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(E186A mutant)20.56 nM+/-2.05125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(P189A mutant)31.78 nM+/-4.12125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(G114A mutant)5.33 nM+/-0.31125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(G109A mutant)3.71 nM+/-0.36125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(G183A mutant)114.72 nM+/-13.6125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(P187A mutant)40.83 nM+/-4.79125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(W184A mutant)16.88 nM+/-0.99125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(N190A mutant)34.07 nM+/-2.77125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(V107A mutant)6.99 nM+/-1.76125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(E199A mutant)27.48 nM+/-1.9125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(I116A mutant)35.10 nM+/-4.4125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(L314A mutant)10.99 nM+/-0.82125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(R115A mutant)11.52 nM+/-0.54125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(E194A mutant)47.59 nM+/-7.6125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(F311A mutant)1.83 nM+/-0.29125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(G196A mutant)21.46 nM+/-4.19125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(C195A mutant)0.40 nM+/-0.08125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(K331A mutant)4.49 nM+/-0.74125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(V197A mutant)9.40 nM+/-1.29125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(L316A mutant)29.31 nM+/-0.95125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
(D192A mutant)38.06 nM+/-3.08125I-HEAT(70 pM)Ragnarsson,L. et al. (2013)
R. norvegicus150nMHEATSharpe,I.A. et al. (2003)
α1B-adrenocD. rerio(α1Bb E327D/S330F mutant )88.51 nM+/-11.143H-prazosin (0.5 nM)Dutt et al. (2019)

EC50: Adrenoceptors

TargetOrganismEC50Ref
α1A-adrenoceptorM. auratus(S318A mutant)19.03 nM+/-3.17Ragnarsson,L. et al. (2013)
(D327A mutnat)6.85 nM+/-1.97Ragnarsson,L. et al. (2013)
(F330A mutant)38.54 nM+/-5.49Ragnarsson,L. et al. (2013)
(W307A mutant)1394.13 nM+/-622.07Ragnarsson,L. et al. (2013)
(C118A mutant)3336.83 nM+/-843.23Ragnarsson,L. et al. (2013)
(K324A mutant)34.52 nM+/-3.97Ragnarsson,L. et al. (2013)
(WT)11.67 nM+/-0.61Ragnarsson,L. et al. (2013)
(F310A mutant)24951.90 nM+/-5055Ragnarsson,L. et al. (2013)
(Y110A mutant)3840.02 nM+/-995.14Ragnarsson,L. et al. (2013)
(E186A mutant)3065.49 nM+/-1120.5Ragnarsson,L. et al. (2013)
(G114A mutant)188.22 nM+/-9.51Ragnarsson,L. et al. (2013)
(G109A mutant)13.72 nM+/-1.65Ragnarsson,L. et al. (2013)
(G183A mutant)3280.64 nM+/-312.35Ragnarsson,L. et al. (2013)
(V107A mutant)11.64 nM+/-1.45Ragnarsson,L. et al. (2013)
(F311A mutant)1337.03 nM+/-182.22Ragnarsson,L. et al. (2013)
(C195A mutant)19195.40 nM+/-846.22Ragnarsson,L. et al. (2013)
(K331A mutant)9.85 nM+/-1.19Ragnarsson,L. et al. (2013)
α1B-adrenoceptorM. auratus1.56 μM+/-0.17Dutt et al. (2019)

Kd: Adrenoceptors

TargetOrganismKdRef
α1A-adrenoceptorM. auratus(S318A mutant)1.63 nM+/-0.23Ragnarsson,L. et al. (2013)
(G317A mutant)1.27 nM+/-0.059Ragnarsson,L. et al. (2013)
(D327A mutnat)1.11 nM+/-0.11Ragnarsson,L. et al. (2013)
(F330A mutant)1.02 nM+/-0.071Ragnarsson,L. et al. (2013)
(F320A mutant)1.83 nM+/-0.33Ragnarsson,L. et al. (2013)
(L319A mutant)0.75 nM+/-0.063Ragnarsson,L. et al. (2013)
(L108A mutant)0.60 nM+/-0.024Ragnarsson,L. et al. (2013)
(F334A mutant)2.07 nM+/-0.22Ragnarsson,L. et al. (2013)
(W307A mutant)NDRagnarsson,L. et al. (2013)
(V329A mutant)0.92 nM+/-0.21Ragnarsson,L. et al. (2013)
(P326A mutant)0.70 nM+/-0.024Ragnarsson,L. et al. (2013)
(D191A mutant)1.31 nM+/-0.08Ragnarsson,L. et al. (2013)
(F202A mutant)1.38 nM+/-0.28Ragnarsson,L. et al. (2013)
(K185A mutant)1.21 nM+/-0.18Ragnarsson,L. et al. (2013)
(P201A mutant)0.47 nM+/-0.037Ragnarsson,L. et al. (2013)
(K193A mutant)0.77 nM+/-0.063Ragnarsson,L. et al. (2013)
(T198A mutant)1.27 nM+/-0.16Ragnarsson,L. et al. (2013)
(C118A mutant)2.53 nM+/-0.89Ragnarsson,L. et al. (2013)
(S321A mutant)0.74 nM+/-0.054Ragnarsson,L. et al. (2013)
(P325A mutant)0.77 nM+/-0.022Ragnarsson,L. et al. (2013)
(K324A mutant)0.56 nM+/-0.017Ragnarsson,L. et al. (2013)
(WT)0.76 nM+/-0.48Ragnarsson,L. et al. (2013)
(L323A mutant)1.85 nM+/-0.35Ragnarsson,L. et al. (2013)
(F310A mutant)4.36 nM+/-0.31Ragnarsson,L. et al. (2013)
(T322A mutant)1.04 nM+/-0.0043Ragnarsson,L. et al. (2013)
(Y110A mutant)0.67 nM+/-0.26Ragnarsson,L. et al. (2013)
(W111A mutant)0.29 nM+/-0.047Ragnarsson,L. et al. (2013)
(V112A mutant)0.66 nM+/-0.066Ragnarsson,L. et al. (2013)
(L113A mutant)0.42 nM+/-0.054Ragnarsson,L. et al. (2013)
(P180A mutant)1.94 nM+/-0.077Ragnarsson,L. et al. (2013)
(L181A mutant)1.48 nM+/-0.24Ragnarsson,L. et al. (2013)
(L182A mutant)1.04 nM+/-0.19Ragnarsson,L. et al. (2013)
(E200A mutant)0.60 nM+/-0.062Ragnarsson,L. et al. (2013)
(E186A mutant)NDRagnarsson,L. et al. (2013)
(P189A mutant)0.94 nM+/-0.064Ragnarsson,L. et al. (2013)
(G114A mutant)0.096 nM+/-0.0097Ragnarsson,L. et al. (2013)
(G109A mutant)0.085 nM+/-0.012Ragnarsson,L. et al. (2013)
(G183A mutant)3.17 nM+/-0.61Ragnarsson,L. et al. (2013)
(P187A mutant)1.02 nM+/-0.026Ragnarsson,L. et al. (2013)
(W184A mutant)0.72 nM+/-0.11Ragnarsson,L. et al. (2013)
(N190A mutant)0.62 nM+/-0.16Ragnarsson,L. et al. (2013)
(V107A mutant)0.22 nM+/-0.0088Ragnarsson,L. et al. (2013)
(E199A mutant)1.07 nM+/-0.0028Ragnarsson,L. et al. (2013)
(I116A mutant)0.54 nM+/-0.043Ragnarsson,L. et al. (2013)
(L314A mutant)2.13 nM+/-0.3Ragnarsson,L. et al. (2013)
(R115A mutant)0.29 nM+/-0.022Ragnarsson,L. et al. (2013)
(E194A mutant)1.29 nM+/-0.24Ragnarsson,L. et al. (2013)
(F311A mutant)5.45 nM+/-0.92Ragnarsson,L. et al. (2013)
(G196A mutant)0.62 nM+/-0.13Ragnarsson,L. et al. (2013)
(C195A mutant)1.00 nM+/-0.29Ragnarsson,L. et al. (2013)
(K331A mutant)0.76 nM+/-0.27Ragnarsson,L. et al. (2013)
(V197A mutant)0.70 nM+/-0.026Ragnarsson,L. et al. (2013)
(L316A mutant)1.13 nM+/-0.3Ragnarsson,L. et al. (2013)
(D192A mutant)1.10 nM+/-0.098Ragnarsson,L. et al. (2013)

Synthetic variants
TIA[I8A]FNWRCCLAPACRRNHKKFC(nh2)
TIA[L7A]FNWRCCAIPACRRNHKKFC(nh2)
TIA[N2A]FAWRCCLIPACRRNHKKFC(nh2)
TIA[R12A]FNWRCCLIPACARNHKKFC(nh2)
TIA[R4A]FNWACCLIPACRRNHKKFC(nh2)
TIA[W3A]FNARCCLIPACRRNHKKFC(nh2)
TIA[del1-2]WRCCLIPACRRNHKKFC(nh2)
TIA[del1-3]RCCLIPACRRNHKKFC(nh2)
TIA[del1-4]CCLIPACRRNHKKFC(nh2)
TIA[del1]NWRCCLIPACRRNHKKFC(nh2)
TIA[del6-19]FNWRC(nh2)
TIA[del7-19]FNWRCC(nh2)

References
Sharpe,I.A., Gehrmann,J., Loughnan,M.L., Thomas,L., Adams,D.A., Atkins,A., Palant,E., Craik,D.J., Adams,D.J., Alewood,P.F. and Lewis,R.J. (2001) Two new classes of conopeptides inhibit the alpha1-adrenoceptor and noradrenaline transporter Nat. Neurosci. 4:902-907
Sharpe,I.A., Thomas,L., Loughnan,M., Motin,L., Palant,E., Croker,D.E., Alewood,D., Chen,S., Graham,R.M., Alewood,P.F., Adams,D.J. and Lewis,R.J. (2003) Allosteric alpha 1-adrenoreceptor antagonism by the conopeptide rho-TIA J. Biol. Chem. 278:34451-34457
Chen,Z., Rogge,G., Hague,C., Alewood,D., Colless,B., Lewis,R.J. and Minneman,K.P. (2004) Subtype-selective noncompetitive or competitive inhibition of human alpha1-adrenergic receptors by rho-TIA J. Biol. Chem. 279:35326-35333
Lima,V., Mueller,A., Kamikihara,S.Y., Raymundi,V., Alewood,D., Lewis,R.J., Chen,Z., Minneman,K.P. and Pupo,A.S. (2005) Differential antagonism by conotoxin rho-TIA of contractions mediated by distinct alpha1-adrenoceptor subtypes in rat vas deferens, spleen and aorta Eur. J. Pharmacol. 508:183-192
Ragnarsson,L., Wang,C.I., Andersson,A., Fajarningsih,D., Monks,T., Brust,A., Rosengren,K.J. and Lewis,R.J. (2013) Conopeptide ρ-TIA defines a new allosteric site on the extracellular surface of the α1B-adrenoceptor. J. Biol. Chem. 288:1814-1827
Patil, N.A., Karas, J.A., Wade, J.D., Hossain, M.A. and Tailhades, J. (2019) Rapid Photolysis-Mediated Folding of Disulfide-Rich Peptides Chemistry–A European Journal 25:8599-8603
Dutt, M., Dutertre, S., Jin, A.H., Lavergne, V., Alewood, P.F. and Lewis, R.J. (2019) Venomics reveals venom complexity of the piscivorous cone snail, Conus tulipa Marine drugs 17:71
Dutt, M., Giacomotto, J., Ragnarsson, L., Andersson, Å., Brust, A., Dekan, Z., Alewood, P.F. and Lewis, R.J. (2019) The α 1-adrenoceptor inhibitor ρ-TIA facilitates net hunting in piscivorous Conus tulipa Scientific reports 9:17841

Internal links
Protein Precursor TIA precursor (8074)
TIA precursor (8075)
Nucleic acids
Structure SOLUTION STRUCTURE OF TIA
High-resolution solution NMR structure of the rho-conotoxin TIA

External links
Ncbi 2LR9_A, P58811

Tools