KGX11_CENNO
ID KGX11_CENNO Reviewed; 62 AA.
AC Q86QT3; Q9GQ92;
DT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 25-MAY-2022, entry version 81.
DE RecName: Full=Potassium channel toxin gamma-KTx 1.1 {ECO:0000303|PubMed:12459475};
DE AltName: Full=Ergtoxin {ECO:0000303|PubMed:10224238};
DE Short=CnErg1 {ECO:0000303|PubMed:12459475};
DE Short=CnErgTx1 {ECO:0000303|PubMed:12459475};
DE Short=ErgTx {ECO:0000303|PubMed:10224238};
DE Short=ErgTx1 {ECO:0000303|PubMed:12459475};
DE Flags: Precursor;
OS Centruroides noxius (Mexican scorpion).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida;
OC Scorpiones; Buthida; Buthoidea; Buthidae; Centruroides.
OX NCBI_TaxID=6878;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 21-62, AND NOMENCLATURE.
RC TISSUE=Venom gland;
RX PubMed=12459475; DOI=10.1016/s0014-5793(02)03652-9;
RA Corona M., Gurrola G.B., Merino E., Cassulini R.R., Valdez-Cruz N.A.,
RA Garcia B., Ramirez-Dominguez M.E., Coronas F.I., Zamudio F.Z., Wanke E.,
RA Possani L.D.;
RT "A large number of novel Ergtoxin-like genes and ERG K+-channels blocking
RT peptides from scorpions of the genus Centruroides.";
RL FEBS Lett. 532:121-126(2002).
RN [2]
RP PROTEIN SEQUENCE OF 21-62, FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=10224238; DOI=10.1096/fasebj.13.8.953;
RA Gurrola G.B., Rosati B., Rocchetti M., Pimienta G., Zaza A., Arcangeli A.,
RA Olivotto M., Possani L.D., Wanke E.;
RT "A toxin to nervous, cardiac, and endocrine ERG K+ channels isolated from
RT Centruroides noxius scorpion venom.";
RL FASEB J. 13:953-962(1999).
RN [3]
RP SEQUENCE REVISION TO 54 AND 61-62, AND MASS SPECTROMETRY.
RX PubMed=11023354; DOI=10.1016/s0014-5793(00)01891-3;
RA Scaloni A., Bottiglieri C., Ferrara L., Corona M., Gurrola G.B.,
RA Batista C.V.F., Wanke E., Possani L.D.;
RT "Disulfide bridges of ergtoxin, a member of a new sub-family of peptide
RT blockers of the ether-a-go-go-related K+ channel.";
RL FEBS Lett. 479:156-157(2000).
RN [4]
RP ERRATUM OF PUBMED:11023354.
RA Scaloni A., Bottiglieri C., Ferrara L., Corona M., Gurrola G.B.,
RA Batista C.V.F., Wanke E., Possani L.D.;
RL FEBS Lett. 481:308-308(2000).
RN [5]
RP FUNCTION.
RX PubMed=11755529; DOI=10.1016/s0014-5793(01)03218-5;
RA Pardo-Lopez L., Garcia-Valdes J., Gurrola G.B., Robertson G.A.,
RA Possani L.D.;
RT "Mapping the receptor site for ergtoxin, a specific blocker of ERG
RT channels.";
RL FEBS Lett. 510:45-49(2002).
RN [6]
RP FUNCTION.
RX PubMed=11864985; DOI=10.1074/jbc.m200460200;
RA Pardo-Lopez L., Zhang M., Liu J., Jiang M., Possani L.D., Tseng G.N.;
RT "Mapping the binding site of a human ether-a-go-go-related gene-specific
RT peptide toxin (ErgTx) to the channel's outer vestibule.";
RL J. Biol. Chem. 277:16403-16411(2002).
RN [7]
RP FUNCTION.
RX PubMed=12860380; DOI=10.1016/s0014-5793(03)00662-8;
RA Milnes J.T., Dempsey C.E., Ridley J.M., Crociani O., Arcangeli A.,
RA Hancox J.C., Witchel H.J.;
RT "Preferential closed channel blockade of HERG potassium currents by
RT chemically synthesised BeKm-1 scorpion toxin.";
RL FEBS Lett. 547:20-26(2003).
RN [8]
RP FUNCTION.
RX PubMed=16497878; DOI=10.1124/mol.105.019729;
RA Restano-Cassulini R., Korolkova Y.V., Diochot S., Gurrola G., Guasti L.,
RA Possani L.D., Lazdunski M., Grishin E.V., Arcangeli A., Wanke E.;
RT "Species diversity and peptide toxins blocking selectivity of ether-a-go-
RT go-related gene subfamily K+ channels in the central nervous system.";
RL Mol. Pharmacol. 69:1673-1683(2006).
RN [9]
RP FUNCTION, AND SYNTHESIS OF 21-62.
RX PubMed=17369411; DOI=10.1529/biophysj.106.101956;
RA Hill A.P., Sunde M., Campbell T.J., Vandenberg J.I.;
RT "Mechanism of block of the hERG K+ channel by the scorpion toxin CnErg1.";
RL Biophys. J. 92:3915-3929(2007).
RN [10]
RP MUTAGENESIS OF MET-55, AND FUNCTION.
RC TISSUE=Venom;
RX PubMed=20600425; DOI=10.1016/j.peptides.2010.06.018;
RA Jimenez-Vargas J.M., Restano-Cassulini R., Quintero-Hernandez V.,
RA Gurrola G.B., Possani L.D.;
RT "Recombinant expression of the toxic peptide ErgTx1 and role of Met35 on
RT its stability and function.";
RL Peptides 32:560-567(2011).
RN [11]
RP MUTAGENESIS OF GLN-38 AND ALA-62.
RX PubMed=23103547; DOI=10.1016/j.bbrc.2012.10.065;
RA Wang X., Jimenez-Vargas J.M., Xu C., Possani L.D., Zhu S.;
RT "Positive selection-guided mutational analysis revealing two key functional
RT sites of scorpion ERG K(+) channel toxins.";
RL Biochem. Biophys. Res. Commun. 429:111-116(2012).
RN [12]
RP STRUCTURE BY NMR OF 21-62, DISULFIDE BONDS, BINDING SITE LYS33, AND
RP SYNTHESIS OF 21-62.
RX PubMed=12650941; DOI=10.1016/s0014-5793(03)00216-3;
RA Torres A.M., Bansal P., Alewood P.F., Bursill J.A., Kuchel P.W.,
RA Vandenberg J.I.;
RT "Solution structure of CnErg1 (Ergtoxin), a HERG specific scorpion toxin.";
RL FEBS Lett. 539:138-142(2003).
RN [13]
RP STRUCTURE BY NMR OF 21-62, AND DISULFIDE BONDS.
RX PubMed=15211519; DOI=10.1002/prot.20102;
RA Frenal K., Xu C.Q., Wolff N., Wecker K., Gurrola G.B., Zhu S.-Y., Chi C.W.,
RA Possani L.D., Tytgat J., Delepierre M.;
RT "Exploring structural features of the interaction between the scorpion
RT toxinCnErg1 and ERG K+ channels.";
RL Proteins 56:367-375(2004).
CC -!- FUNCTION: Blocks human and rat Kv11.1/KCNH2/ERG1 and Kv11.3/KCNH7/ERG3,
CC as well as rat (but not human) Kv11.2/KCNH6/ERG2 (PubMed:11755529,
CC PubMed:11864985, PubMed:16497878, PubMed:17369411, PubMed:20600425) by
CC binding to channel outer vestibule (S5P domain) with a 1:1
CC stoichiometry (PubMed:11755529, PubMed:11864985, PubMed:17369411,
CC PubMed:20600425). Inhibition data are the following: hERG1 (reversible,
CC IC(50)~7 nM) (PubMed:11755529, PubMed:11864985, PubMed:16497878,
CC PubMed:17369411, PubMed:20600425), rERG1 (reversible, Kd=6.8 nM)
CC (PubMed:16497878), rERG2 (irreversible, Kd=2.8 nM) (PubMed:16497878),
CC hERG3 (irreversible, Kd=4.05 nM) (PubMed:16497878) and rERG3
CC (reversible, Kd=38.1 nM) (PubMed:16497878) potassium channels. The
CC toxin potency is not affected by elevating potassium ion concentration
CC from 2 to 98 mM (PubMed:11864985). This toxin only blocks channels in a
CC closed state (PubMed:12860380). At high toxin concentrations, block of
CC Kv11.1/KCNH2/ERG1 macroscopic current is incomplete (93.5%). This
CC suggests a kinetic mechanism model with two different states of toxin-
CC channel binding (T+C=TC*=TC; in the TC* state, the toxin binds the
CC channel but does not occlude the pore, whereas in the TC state the
CC toxin binds and occludes the pore). In this model, incomplete block is
CC explained by the relatively fast dissociation rate from the blocked
CC channel conformation (TC) relative to the rate of conversion of the
CC toxin-channel encounter complex (TC*) to the blocked channel
CC conformation (TC) (PubMed:17369411). {ECO:0000269|PubMed:10224238,
CC ECO:0000269|PubMed:11755529, ECO:0000269|PubMed:11864985,
CC ECO:0000269|PubMed:12860380, ECO:0000269|PubMed:16497878,
CC ECO:0000269|PubMed:17369411, ECO:0000269|PubMed:20600425}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:10224238}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC -!- DOMAIN: Has the CSalpha/beta fold, which comprises one or two short
CC alpha helices connected to anti-parallel beta-sheets stabilized by
CC three or four disulfide bonds. {ECO:0000269|PubMed:12650941,
CC ECO:0000269|PubMed:15211519}.
CC -!- PTM: After protein storage at -20 Celsius degrees during a couple of
CC months, the Met-55 of a small number of toxins is naturally oxidized.
CC This oxidized form is about three orders of magnitude less efficient
CC (IC(50)=15 uM) than non-oxidized form. {ECO:0000269|PubMed:20600425}.
CC -!- MASS SPECTROMETRY: Mass=4730.8; Mass_error=0.4; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:11023354};
CC -!- MISCELLANEOUS: The affinity of the toxin for the channel decreases as
CC temperature increases (Kd=7.3 nM and Kd=64 nM at 22 and 37 degrees
CC Celsius, respectively), likely due to changes in the structure of the
CC channel binding site. {ECO:0000269|PubMed:17369411}.
CC -!- MISCELLANEOUS: Does not affect the function of either mouse EAG/KCNH1
CC or ELK1 channels at concentration of 200 nM (PubMed:11755529). Does not
CC inhibit hKv1.4/KCNA4, hKv4.3/KCND3, hKv2.1/KCNB1 and rKv7.1/KCNQ1
CC potassium channels at concentration of 50 nM (PubMed:11864985). Does
CC not inhibit human Kv11.2/KCNH6/ERG2 (PubMed:16497878).
CC {ECO:0000269|PubMed:11755529, ECO:0000269|PubMed:11864985,
CC ECO:0000269|PubMed:16497878}.
CC -!- SIMILARITY: Belongs to the ergtoxin family. Gamma-KTx 1 subfamily.
CC {ECO:0000305}.
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DR EMBL; AY164271; AAO22234.1; -; mRNA.
DR EMBL; AF288205; AAG38523.1; -; mRNA.
DR PDB; 1NE5; NMR; -; A=21-62.
DR PDB; 1PX9; NMR; -; A=21-62.
DR PDBsum; 1NE5; -.
DR PDBsum; 1PX9; -.
DR AlphaFoldDB; Q86QT3; -.
DR SMR; Q86QT3; -.
DR EvolutionaryTrace; Q86QT3; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0019870; F:potassium channel inhibitor activity; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR Gene3D; 3.30.30.10; -; 1.
DR InterPro; IPR012622; Ergtoxin.
DR InterPro; IPR036574; Scorpion_toxin-like_sf.
DR Pfam; PF08086; Toxin_17; 1.
DR SUPFAM; SSF57095; SSF57095; 1.
DR PROSITE; PS60026; ERGTX; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Knottin; Neurotoxin;
KW Potassium channel impairing toxin; Secreted; Signal; Toxin;
KW Voltage-gated potassium channel impairing toxin.
FT SIGNAL 1..20
FT /evidence="ECO:0000269|PubMed:10224238"
FT CHAIN 21..62
FT /note="Potassium channel toxin gamma-KTx 1.1"
FT /id="PRO_0000035362"
FT SITE 33
FT /note="May represent the binding site"
FT /evidence="ECO:0000305|PubMed:12650941"
FT SITE 55
FT /note="Key residue on the interacting surface with the
FT channel"
FT /evidence="ECO:0000305|PubMed:20600425"
FT DISULFID 25..43
FT /evidence="ECO:0000269|PubMed:12650941,
FT ECO:0000269|PubMed:15211519"
FT DISULFID 31..54
FT /evidence="ECO:0000269|PubMed:12650941,
FT ECO:0000269|PubMed:15211519"
FT DISULFID 40..59
FT /evidence="ECO:0000269|PubMed:12650941,
FT ECO:0000269|PubMed:15211519"
FT DISULFID 44..61
FT /evidence="ECO:0000269|PubMed:12650941,
FT ECO:0000269|PubMed:15211519"
FT MUTAGEN 38
FT /note="Q->A: 6-fold reduction in affinity for
FT Kv11.1/KCNH2/ERG1 potassium channel (Kd=72.9 nM)."
FT /evidence="ECO:0000269|PubMed:23103547"
FT MUTAGEN 55
FT /note="M->A: 30-fold reduction in affinity for
FT Kv11.1/KCNH2/ERG1 potassium channel (Kd=303.4 nM)."
FT /evidence="ECO:0000269|PubMed:20600425"
FT MUTAGEN 62
FT /note="A->T: No change in affinity for Kv11.1/KCNH2/ERG1
FT potassium channel (Kd=14.2 nM)."
FT /evidence="ECO:0000269|PubMed:23103547"
FT HELIX 25..27
FT /evidence="ECO:0007829|PDB:1NE5"
FT STRAND 33..35
FT /evidence="ECO:0007829|PDB:1NE5"
FT HELIX 38..47
FT /evidence="ECO:0007829|PDB:1NE5"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:1NE5"
FT STRAND 52..57
FT /evidence="ECO:0007829|PDB:1NE5"
FT STRAND 59..61
FT /evidence="ECO:0007829|PDB:1NE5"
SQ SEQUENCE 62 AA; 6970 MW; 53F88F4B9F187E37 CRC64;
MKVLILIMII ASLMIMGVEM DRDSCVDKSR CAKYGYYQEC QDCCKNAGHN GGTCMFFKCK
CA
