ID KAX61_PANIM Reviewed; 35 AA. AC Q10726; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 22-FEB-2023, entry version 108. DE RecName: Full=Potassium channel toxin alpha-KTx 6.1; DE AltName: Full=PiTX-K-gamma {ECO:0000303|PubMed:8913348}; DE AltName: Full=Potassium channel-blocking toxin 1; DE Short=Pi-1; DE Short=Pi1 {ECO:0000303|PubMed:8645186, ECO:0000303|PubMed:9001397}; OS Pandinus imperator (Emperor scorpion). OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; OC Scorpiones; Iurida; Scorpionoidea; Scorpionidae; Pandininae; Pandinus. OX NCBI_TaxID=55084; RN [1] RP PROTEIN SEQUENCE, FUNCTION, DISULFIDE BONDS, AND SUBCELLULAR LOCATION. RC TISSUE=Venom; RX PubMed=8645186; DOI=10.1042/bj3150977; RA Olamendi-Portugal T., Gomez-Lagunas F., Gurrola G.B., Possani L.D.; RT "A novel structural class of K+-channel blocking toxin from the scorpion RT Pandinus imperator."; RL Biochem. J. 315:977-981(1996). RN [2] RP PROTEIN SEQUENCE, FUNCTION, AND SUBCELLULAR LOCATION. RC TISSUE=Venom; RX PubMed=8913348; RA Rogowski R.S., Collins J.H., O'Neill T.J., Gustafson T.A., Werkman T.R., RA Rogawski M.A., Tenenholz T.C., Weber D.J., Blaustein M.P.; RT "Three new toxins from the scorpion Pandinus imperator selectively block RT certain voltage-gated K+ channels."; RL Mol. Pharmacol. 50:1167-1177(1996). RN [3] RP FUNCTION. RX PubMed=9001397; DOI=10.1016/s0014-5793(96)01387-7; RA Gomez-Lagunas F., Olamendi-Portugal T., Possani L.D.; RT "Block of ShakerB K+ channels by Pi1, a novel class of scorpion toxin."; RL FEBS Lett. 400:197-200(1997). RN [4] RP FUNCTION. RX PubMed=9464266; DOI=10.1006/bbrc.1997.8018; RA Peter M. Jr., Varga Z., Panyi G., Bene L., Damjanovich S., Pieri C., RA Possani L.D., Gaspar R. Jr.; RT "Pandinus imperator scorpion venom blocks voltage-gated K+ channels in RT human lymphocytes."; RL Biochem. Biophys. Res. Commun. 242:621-625(1998). RN [5] RP FUNCTION, TOXIC DOSE, AND SYNTHESIS. RX PubMed=10931199; DOI=10.1046/j.1432-1327.2000.01577.x; RA Fajloun Z., Carlier E., Lecomte C., Geib S., Di Luccio E., Bichet D., RA Mabrouk K., Rochat H., De Waard M., Sabatier J.M.; RT "Chemical synthesis and characterization of Pi1, a scorpion toxin from RT Pandinus imperator active on K+ channels."; RL Eur. J. Biochem. 267:5149-5155(2000). RN [6] RP FUNCTION. RX PubMed=11527975; DOI=10.1074/jbc.m106981200; RA Shakkottai V.G., Regaya I., Wulff H., Fajloun Z., Tomita H., Fathallah M., RA Cahalan M.D., Gargus J.J., Sabatier J.M., Chandy K.G.; RT "Design and characterization of a highly selective peptide inhibitor of the RT small conductance calcium-activated K+ channel, SkCa2."; RL J. Biol. Chem. 276:43145-43151(2001). RN [7] RP MUTAGENESIS OF ARG-5; ARG-12; LYS-24; LYS-31 AND TYR-33, AND SITES. RX PubMed=12962541; DOI=10.1042/bj20030115; RA Mouhat S., Mosbah A., Visan V., Wulff H., Delepierre M., Darbon H., RA Grissmer S., De Waard M., Sabatier J.M.; RT "The 'functional' dyad of scorpion toxin Pi1 is not itself a prerequisite RT for toxin binding to the voltage-gated Kv1.2 potassium channels."; RL Biochem. J. 377:25-36(2004). RN [8] RP STRUCTURE BY NMR, AND DISULFIDE BONDS. RX PubMed=9054572; DOI=10.1021/bi9617116; RA Delepierre M., Prochnicka-Chalufour A., Possani L.D.; RT "A novel potassium channel blocking toxin from the scorpion Pandinus RT imperator: a 1H NMR analysis using a nano-NMR probe."; RL Biochemistry 36:2649-2658(1997). RN [9] RP STRUCTURE BY NMR, AND DISULFIDE BONDS. RX PubMed=16247791; DOI=10.1002/prot.20681; RA Carrega L., Mosbah A., Ferrat G., Beeton C., Andreotti N., Mansuelle P., RA Darbon H., De Waard M., Sabatier J.M.; RT "The impact of the fourth disulfide bridge in scorpion toxins of the alpha- RT KTx6 subfamily."; RL Proteins 61:1010-1023(2005). CC -!- FUNCTION: Potently and reversibly inhibits the insect voltage-gated CC Shaker (Sh) potassium channel (isoform alpha (B)), the mammalian CC voltage-gated potassium channels Kv1.2/KCNA2 (IC(50)=0.44 nM), and the CC calcium-activated potassium channel KCa2.3/KCNN3 (Kd=330 nM) CC (PubMed:9001397, PubMed:10931199, PubMed:11527975). Its effect on CC Kv1.3/KCNA3 is controversial, since this channel is voltage- CC independently inhibited in PubMed:9464266, but is not affected in CC PubMed:10931199. Furthermore, this toxin competes with apamin (a small CC conductance calcium-activated potassium channel inhibitor) for binding CC to rat brain synaptosomes. {ECO:0000269|PubMed:10931199, CC ECO:0000269|PubMed:11527975, ECO:0000269|PubMed:8645186, CC ECO:0000269|PubMed:9001397, ECO:0000269|PubMed:9464266}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:8645186, CC ECO:0000269|PubMed:8913348}. CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. CC {ECO:0000305|PubMed:8645186, ECO:0000305|PubMed:8913348}. CC -!- DOMAIN: Has the structural arrangement of an alpha-helix connected to a CC beta-sheet by disulfide bonds (CSalpha/beta). CC {ECO:0000269|PubMed:16247791}. CC -!- DOMAIN: The alpha-helical domain may play a key role in the recognition CC of SK channels. CC -!- DOMAIN: The beta-sheet structure may be involved in bioactivity on Kv CC channels. CC -!- TOXIC DOSE: LD(50) is 10 ug/kg by intraperitoneal injection into mice. CC {ECO:0000269|PubMed:10931199}. CC -!- MISCELLANEOUS: Pi1 analog that is synthesized with a phosphorylation at CC Tyr-33 (P-Pi1) suffers a 200-fold decrease in LD(50), a 200-fold CC decrease of potency in competition assay with apamin, and a 58-fold CC decrease in inhibiting Kv1.2/KCNA2 channels. CC -!- MISCELLANEOUS: Negative results: does not or very weakly inhibits CC KCa2.2/KCNN2 (Kd> 1 uM) and Kv1.1/KCNA1 (no effect observed at 5 uM). CC {ECO:0000269|PubMed:10931199, ECO:0000269|PubMed:8913348}. CC -!- SIMILARITY: Belongs to the short scorpion toxin superfamily. Potassium CC channel inhibitor family. Alpha-KTx 06 subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR PIR; S69599; S69599. DR PDB; 1WZ5; NMR; -; A=1-35. DR PDBsum; 1WZ5; -. DR AlphaFoldDB; Q10726; -. DR SMR; Q10726; -. DR EvolutionaryTrace; Q10726; -. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0008200; F:ion channel inhibitor activity; IEA:InterPro. DR GO; GO:0015459; F:potassium channel regulator activity; IEA:UniProtKB-KW. DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW. DR Gene3D; 3.30.30.10; Knottin, scorpion toxin-like; 1. DR InterPro; IPR036574; Scorpion_toxin-like_sf. DR InterPro; IPR001947; Scorpion_toxinS_K_inh. DR Pfam; PF00451; Toxin_2; 1. DR SUPFAM; SSF57095; Scorpion toxin-like; 1. DR PROSITE; PS01138; SCORP_SHORT_TOXIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Calcium-activated potassium channel impairing toxin; KW Direct protein sequencing; Disulfide bond; Ion channel impairing toxin; KW Neurotoxin; Potassium channel impairing toxin; Secreted; Toxin; KW Voltage-gated potassium channel impairing toxin. FT PEPTIDE 1..35 FT /note="Potassium channel toxin alpha-KTx 6.1" FT /evidence="ECO:0000269|PubMed:8645186, FT ECO:0000269|PubMed:8913348" FT /id="PRO_0000044912" FT SITE 5 FT /note="Part of the basic ring which may anchor to the FT external vestibule of the K(+) channel" FT /evidence="ECO:0000269|PubMed:12962541" FT SITE 12 FT /note="Part of the basic ring which may anchor to the FT external vestibule of the K(+) channel" FT /evidence="ECO:0000269|PubMed:12962541" FT SITE 24 FT /note="Basic residue of the functional dyad" FT /evidence="ECO:0000269|PubMed:12962541" FT SITE 28 FT /note="Part of the basic ring which may anchor to the FT external vestibule of the K(+) channel" FT /evidence="ECO:0000305|PubMed:12962541" FT SITE 31 FT /note="Part of the basic ring which may anchor to the FT external vestibule of the K(+) channel" FT /evidence="ECO:0000269|PubMed:12962541" FT SITE 33 FT /note="Aromatic residue of the functional dyad" FT /evidence="ECO:0000269|PubMed:12962541" FT DISULFID 4..25 FT /evidence="ECO:0000269|PubMed:16247791, FT ECO:0000269|PubMed:8645186, ECO:0000269|PubMed:9054572, FT ECO:0000312|PDB:1WZ5" FT DISULFID 10..30 FT /evidence="ECO:0000269|PubMed:16247791, FT ECO:0000269|PubMed:8645186, ECO:0000269|PubMed:9054572, FT ECO:0000312|PDB:1WZ5" FT DISULFID 14..32 FT /evidence="ECO:0000269|PubMed:16247791, FT ECO:0000269|PubMed:8645186, ECO:0000269|PubMed:9054572, FT ECO:0000312|PDB:1WZ5" FT DISULFID 20..35 FT /evidence="ECO:0000269|PubMed:16247791, FT ECO:0000269|PubMed:8645186, ECO:0000269|PubMed:9054572, FT ECO:0000312|PDB:1WZ5" FT MUTAGEN 5 FT /note="R->A: 51-fold decrease in inhibiting Kv1.2/KCNA2 FT channels; when associated with A-12. 479-fold decrease in FT inhibiting Kv1.2/KCNA2 channels; when associated with FT A-31." FT /evidence="ECO:0000269|PubMed:12962541" FT MUTAGEN 12 FT /note="R->A: 51-fold decrease in inhibiting Kv1.2/KCNA2 FT channels; when associated with A-5." FT /evidence="ECO:0000269|PubMed:12962541" FT MUTAGEN 24 FT /note="K->A: 500-fold decrease in LD(50), 600-fold decrease FT of potency in competition assay with apamin, and 17000-fold FT decrease in inhibiting Kv1.2/KCNA2 channels; when FT associated with A-33." FT /evidence="ECO:0000269|PubMed:12962541" FT MUTAGEN 31 FT /note="K->A: 294-fold decrease in inhibiting Kv1.2/KCNA2 FT channels. 479-fold decrease in inhibiting Kv1.2/KCNA2 FT channels; when associated with A-5." FT /evidence="ECO:0000269|PubMed:12962541" FT MUTAGEN 33 FT /note="Y->A: 500-fold decrease in LD(50), 600-fold decrease FT of potency in competition assay with apamin, and FT 17,000-fold decrease in inhibiting Kv1.2/KCNA2 channels; FT when associated with A-24." FT /evidence="ECO:0000269|PubMed:12962541" FT TURN 6..10 FT /evidence="ECO:0007829|PDB:1WZ5" FT HELIX 11..17 FT /evidence="ECO:0007829|PDB:1WZ5" FT STRAND 24..26 FT /evidence="ECO:0007829|PDB:1WZ5" FT STRAND 29..31 FT /evidence="ECO:0007829|PDB:1WZ5" SQ SEQUENCE 35 AA; 3843 MW; 208001C82B2C9800 CRC64; LVKCRGTSDC GRPCQQQTGC PNSKCINRMC KCYGC //