KGX21_MESEU
ID KGX21_MESEU Reviewed; 57 AA.
AC Q9BKB7;
DT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 25-MAY-2022, entry version 87.
DE RecName: Full=Potassium channel toxin gamma-KTx 2.1 {ECO:0000303|PubMed:12459475};
DE AltName: Full=Neurotoxin BeKm-1 {ECO:0000303|PubMed:8617371};
DE Short=BeKm1 {ECO:0000305};
DE Flags: Precursor;
OS Mesobuthus eupeus (Lesser Asian scorpion) (Buthus eupeus).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida;
OC Scorpiones; Buthida; Buthoidea; Buthidae; Mesobuthus.
OX NCBI_TaxID=34648;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 22-57, FUNCTION,
RP MUTAGENESIS OF ARG-48 AND PHE-53, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom, and Venom gland;
RX PubMed=11136720; DOI=10.1074/jbc.m005973200;
RA Korolkova Y.V., Kozlov S.A., Lipkin A.V., Pluzhnikov K.A., Hadley J.K.,
RA Filippov A.K., Brown D.A., Angelo K., Strobaek D., Jespersen T.,
RA Olesen S.-P., Jensen B.S., Grishin E.V.;
RT "An ERG channel inhibitor from the scorpion Buthus eupeus.";
RL J. Biol. Chem. 276:9868-9876(2001).
RN [2]
RP FUNCTION.
RX PubMed=8617371; DOI=10.1016/0014-5793(96)00333-x;
RA Filippov A.K., Kozlov S.A., Pluzhnikov K.A., Grishin E.V., Brown D.A.;
RT "M-type K+ current inhibition by a toxin from the scorpion Buthus eupeus.";
RL FEBS Lett. 384:277-280(1996).
RN [3]
RP FUNCTION.
RX PubMed=12719233; DOI=10.1016/s0006-3495(03)70028-9;
RA Zhang M., Korolkova Y.V., Liu J., Jiang M., Grishin E.V., Tseng G.N.;
RT "BeKm-1 is a HERG-specific toxin that shares the structure with ChTx but
RT the mechanism of action with ErgTx1.";
RL Biophys. J. 84:3022-3036(2003).
RN [4]
RP SYNTHESIS OF 22-57, AND 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 [5]
RP REVIEW, AND ERG1-TOXIN DOCKING MODELING.
RX PubMed=15137031; DOI=10.1002/jmr.667;
RA Korolkova Y.V., Tseng G.N., Grishin E.V.;
RT "Unique interaction of scorpion toxins with the hERG channel.";
RL J. Mol. Recognit. 17:209-217(2004).
RN [6]
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 [7]
RP FUNCTION, AND FUNCTION ON RABBIT HEART.
RX PubMed=21205913; DOI=10.1124/jpet.110.176883;
RA Qu Y., Fang M., Gao B., Chui R.W., Vargas H.M.;
RT "BeKm-1, a peptide inhibitor of human ether-a-go-go-related gene potassium
RT currents, prolongs QTc intervals in isolated rabbit heart.";
RL J. Pharmacol. Exp. Ther. 337:2-8(2011).
RN [8]
RP NOMENCLATURE.
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 [9]
RP CHANNEL-TOXIN INTERACTION MODELING.
RX PubMed=17269718; DOI=10.1021/pr060368g;
RA Yi H., Cao Z., Yin S., Dai C., Wu Y., Li W.;
RT "Interaction simulation of hERG K+ channel with its specific BeKm-1
RT peptide: insights into the selectivity of molecular recognition.";
RL J. Proteome Res. 6:611-620(2007).
RN [10]
RP STRUCTURE BY NMR OF 22-57, DISULFIDE BONDS, AND MUTAGENESIS OF ARG-22;
RP PRO-23; ASP-25; LYS-27; GLU-30; TYR-32; GLN-33; PHE-35; LYS-39; ARG-41;
RP PHE-42; LYS-44; ARG-48; VAL-50; PHE-53; ASP-55 AND PHE-57.
RX PubMed=12151390; DOI=10.1074/jbc.m204083200;
RA Korolkova Y.V., Bocharov E.V., Angelo K., Maslennikov I.V., Grinenko O.V.,
RA Lipkin A.V., Nosyreva E.D., Pluzhnikov K.A., Olesen S.-P., Arseniev A.S.,
RA Grishin E.V.;
RT "New binding site on common molecular scaffold provides HERG channel
RT specificity of scorpion toxin BeKm-1.";
RL J. Biol. Chem. 277:43104-43109(2002).
CC -!- FUNCTION: Blocks human and/or rat Kv11.1/KCNH2/ERG1, Kv11.2/KCNH6/ERG2
CC and Kv11.3/KCNH7/ERG3 by binding to channel outer vestibule (S5P
CC domain) with a 1:1 stoichiometry. Inhibition data are the following:
CC hERG1 (reversible, Kd=7.7 nM (PubMed:16497878), IC(50)=3.3 nM
CC (PubMed:11136720), IC(50)=11.9 nM (PubMed:21205913)), rERG1
CC (reversible, Kd=19 nM) (PubMed:16497878), hERG2 (reversible, Kd=77 nM)
CC (PubMed:16497878), rERG2 (irreversible, Kd=4.2 nM) (PubMed:16497878),
CC hERG3 (reversible, Kd=11.5 nM) (PubMed:16497878) and rERG3 (reversible,
CC Kd=747 nM) (PubMed:16497878) potassium channels. Has also a minimal
CC effect on rat ELK1/KCNH4 potassium channels (9% inhibition at 100 nM
CC (PubMed:15137031)). Both this toxin and CnErgTx1 (AC Q86QT3) share
CC mechanism of action and have overlapping binding sites on ERG1
CC (PubMed:12719233). The potency of these two toxins is not affected by
CC elevating potassium ion concentration from 2 to 98 mM
CC (PubMed:12719233). In addition, at high toxin concentrations, block of
CC ERG1 macroscopic currents by these two toxins is incomplete (88%)
CC (PubMed:12719233). The blockade by this toxin is preferentially closed
CC channel state-dependent, with a component of open, but not inactive
CC state-dependent blockade (PubMed:12860380). This toxin produces a
CC concentration-dependent prolongation of QTc in the isolated rabbit
CC heart (16.3% at 100 nM) (PubMed:21205913).
CC {ECO:0000269|PubMed:11136720, ECO:0000269|PubMed:12719233,
CC ECO:0000269|PubMed:12860380, ECO:0000269|PubMed:16497878,
CC ECO:0000269|PubMed:21205913, ECO:0000269|PubMed:8617371}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:11136720}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305}.
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:12151390}.
CC -!- MISCELLANEOUS: The inhibition potency of the toxin for ERG1 decreases
CC as temperature increases (IC(50)=7.6 nM and IC(50)=15.3 nM at room
CC temperature and 37 degrees Celsius, respectively), likely due to
CC changes in the structure of the channel binding site.
CC {ECO:0000269|PubMed:12860380}.
CC -!- MISCELLANEOUS: The toxin (at 100 nM) does not inhibit hEAG1/KCNH1,
CC hBK/KCa1.1/KCNMA1, hSK1/KCa2.1/KCNN1, rSK2/KCa2.2/KCNN2,
CC hIK/KCa3.1/KCNN4, KCNQ1+KCNE1, KCNQ2+KCNQ3 and KCNQ4 channels
CC (PubMed:11136720). The toxin (at 50 nM) does not inhibit Kv1.2/KCNA2,
CC Kv1.4/KCNA4, Kv2.1/KCNB1, Kv4.3/KCND3, Kir1.1/KCNJ1 (PubMed:15137031).
CC {ECO:0000269|PubMed:11136720, ECO:0000269|PubMed:15137031}.
CC -!- SIMILARITY: Belongs to the short scorpion toxin superfamily. Potassium
CC channel inhibitor family. Gamma-KTx 2 subfamily. {ECO:0000305}.
CC -!- CAUTION: Has been classified as a gamma-KTx toxin due to its molecular
CC target (Kv11/ERG), but may be classified as an alpha-KTx since it
CC shares a high level of homology in both primary and 3D structures with
CC other alpha-KTx scorpion toxins. However, it is noteworthy that surface
CC by which BeKm-1 interacts with ERG1 is formed by residues located in
CC the alpha-helix and the following loop, while the traditional
CC functional site of other alpha-KTxs is formed by residues on the beta-
CC sheet. {ECO:0000305|PubMed:15137031}.
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DR EMBL; AF276623; AAK28021.1; -; mRNA.
DR PDB; 1J5J; NMR; -; A=22-57.
DR PDB; 1LGL; NMR; -; A=22-57.
DR PDBsum; 1J5J; -.
DR PDBsum; 1LGL; -.
DR AlphaFoldDB; Q9BKB7; -.
DR BMRB; Q9BKB7; -.
DR SMR; Q9BKB7; -.
DR EvolutionaryTrace; Q9BKB7; -.
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; -; 1.
DR InterPro; IPR036574; Scorpion_toxin-like_sf.
DR InterPro; IPR001947; Scorpion_toxinS_K_inh.
DR Pfam; PF00451; Toxin_2; 1.
DR SUPFAM; SSF57095; SSF57095; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Neurotoxin; Potassium channel impairing toxin;
KW Secreted; Signal; Toxin; Voltage-gated potassium channel impairing toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000269|PubMed:11136720"
FT CHAIN 22..57
FT /note="Potassium channel toxin gamma-KTx 2.1"
FT /evidence="ECO:0000269|PubMed:11136720"
FT /id="PRO_0000035313"
FT SITE 39
FT /note="Crucial for Kv11/ERG channel binding, plugs its side
FT chain into the channel selectivity filter"
FT /evidence="ECO:0000305|PubMed:12151390,
FT ECO:0000305|PubMed:17269718"
FT SITE 41
FT /note="Crucial for Kv11/ERG channel binding"
FT /evidence="ECO:0000305|PubMed:12151390,
FT ECO:0000305|PubMed:17269718"
FT DISULFID 28..49
FT /evidence="ECO:0000269|PubMed:12151390"
FT DISULFID 34..54
FT /evidence="ECO:0000269|PubMed:12151390"
FT DISULFID 38..56
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 22
FT /note="R->A: 6.7-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 23
FT /note="P->A: 1.7-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 25
FT /note="D->A: 3.4-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 27
FT /note="K->A: 2.7-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 30
FT /note="E->A: 0.8-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 32
FT /note="Y->A: 14.7-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 33
FT /note="Q->A: 2.3-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 35
FT /note="F->A: 8.2-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 39
FT /note="K->A: 86.4-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 41
FT /note="R->A: 70.6-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 42
FT /note="F->A: 52.2-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 44
FT /note="K->A: 14.6-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 48
FT /note="R->A: 7.4-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT MUTAGEN 48
FT /note="R->K: 60% loss of toxicity. No loss of activity;
FT when associated with K-53."
FT /evidence="ECO:0000269|PubMed:11136720,
FT ECO:0000269|PubMed:12151390"
FT MUTAGEN 50
FT /note="V->A: 1.2-fold decrease in affinity to ERG-potassium
FT channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 53
FT /note="F->A: 1.4-fold decrease in affinity to ERG-potassium
FT channels."
FT /evidence="ECO:0000269|PubMed:11136720,
FT ECO:0000269|PubMed:12151390"
FT MUTAGEN 53
FT /note="F->K: No loss of activity. No loss of activity but
FT gain in inhibition of native calcium- activated potassium
FT channels with Kd of about 72 nM; when associated with K-
FT 48."
FT /evidence="ECO:0000269|PubMed:11136720,
FT ECO:0000269|PubMed:12151390"
FT MUTAGEN 55
FT /note="D->A: 1.1-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT MUTAGEN 57
FT /note="F->A: 3.2-fold decrease in affinity to Kv11/ERG
FT potassium channels."
FT /evidence="ECO:0000269|PubMed:12151390"
FT STRAND 23..27
FT /evidence="ECO:0007829|PDB:1J5J"
FT HELIX 31..33
FT /evidence="ECO:0007829|PDB:1J5J"
FT HELIX 34..40
FT /evidence="ECO:0007829|PDB:1J5J"
FT STRAND 45..50
FT /evidence="ECO:0007829|PDB:1J5J"
FT STRAND 53..57
FT /evidence="ECO:0007829|PDB:1J5J"
SQ SEQUENCE 57 AA; 6452 MW; 8B85BF8660816666 CRC64;
MKISFVLLLT LFICSIGWSE ARPTDIKCSE SYQCFPVCKS RFGKTNGRCV NGFCDCF
