ID NA1B_ANTXA Reviewed; 49 AA. AC P01531; V9GZA1; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1988, sequence version 1. DT 22-FEB-2023, entry version 106. DE RecName: Full=Delta-actitoxin-Axm1b {ECO:0000303|PubMed:22683676}; DE Short=Delta-AITX-Axm1b {ECO:0000303|PubMed:22683676}; DE AltName: Full=Anthopleurin-B {ECO:0000303|PubMed:6108877}; DE Short=AP-B {ECO:0000303|PubMed:6108877}; DE Short=ApB {ECO:0000303|PubMed:8621610}; OS Anthopleura xanthogrammica (Giant green sea anemone) (Actinia OS xanthogrammica). OC Eukaryota; Metazoa; Cnidaria; Anthozoa; Hexacorallia; Actiniaria; OC Actiniidae; Anthopleura. OX NCBI_TaxID=6112; RN [1] RP PROTEIN SEQUENCE. RC TISSUE=Nematoblast; RX PubMed=4019448; DOI=10.1016/s0021-9258(17)39403-6; RA Reimer N.S., Yasunobu C.L., Yasunobu K.T., Norton T.R.; RT "Amino acid sequence of the Anthopleura xanthogrammica heart stimulant, RT anthopleurin-B."; RL J. Biol. Chem. 260:8690-8693(1985). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=1629194; DOI=10.1016/s0021-9258(19)49663-4; RA Gallagher M.J., Blumenthal K.M.; RT "Cloning and expression of wild-type and mutant forms of the cardiotonic RT polypeptide anthopleurin B."; RL J. Biol. Chem. 267:13958-13963(1992). RN [3] RP PROTEIN SEQUENCE OF 1-28. RX PubMed=6108877; RA Norton T.R.; RT "Cardiotonic polypeptides from Anthopleura xanthogrammica (Brandt) and A. RT elegantissima (Brandt)."; RL Fed. Proc. 40:21-25(1981). RN [4] RP FUNCTION, MUTAGENESIS OF ARG-12 AND LYS-49, AND SITES ARG-12 AND LYS-49. RX PubMed=8276803; DOI=10.1016/s0021-9258(17)42342-8; RA Gallagher M.J., Blumenthal K.M.; RT "Importance of the unique cationic residues arginine 12 and lysine 49 in RT the activity of the cardiotonic polypeptide anthopleurin B."; RL J. Biol. Chem. 269:254-259(1994). RN [5] RP MUTAGENESIS OF ARG-14 AND LYS-48, AND SITES ARG-14 AND LYS-48. RX PubMed=8288644; DOI=10.1016/s0021-9258(17)42199-5; RA Khera P.K., Blumenthal K.M.; RT "Role of the cationic residues arginine 14 and lysine 48 in the function of RT the cardiotonic polypeptide anthopleurin B."; RL J. Biol. Chem. 269:921-925(1994). RN [6] RP FUNCTION, AND MUTAGENESIS OF ARG-12; ARG-14; LYS-48 AND LYS-49. RX PubMed=7612595; DOI=10.1021/bi00027a003; RA Khera P.K., Benzinger G.R., Lipkind G., Drum C.L., Hanck D.A., RA Blumenthal K.M.; RT "Multiple cationic residues of anthopleurin B that determine high affinity RT and channel isoform discrimination."; RL Biochemistry 34:8533-8541(1995). RN [7] RP MUTAGENESIS OF ASP-7; ASP-9; HIS-34; LYS-37 AND HIS-39, AND SITES ASP-7; RP ASP-9; LYS-34; LYS-37 AND LYS-39. RX PubMed=8639500; DOI=10.1021/bi9528457; RA Khera P.K., Blumenthal K.M.; RT "Importance of highly conserved anionic residues and electrostatic RT interactions in the activity and structure of the cardiotonic polypeptide RT anthopleurin B."; RL Biochemistry 35:3503-3507(1996). RN [8] RP MUTAGENESIS OF PRO-3; ARG-12; PRO-13; ILE-21; PHE-24; ASN-42 AND LYS-49, RP AND SITE PRO-13. RX PubMed=8916901; DOI=10.1021/bi961584d; RA Kelso G.J., Drum C.L., Hanck D.A., Blumenthal K.M.; RT "Role for Pro-13 in directing high-affinity binding of anthopleurin B to RT the voltage-sensitive sodium channel."; RL Biochemistry 35:14157-14164(1996). RN [9] RP MUTAGENESIS OF LEU-18 AND ILE-43, AND SITES LEU-18 AND ILE-43. RX PubMed=8621610; DOI=10.1074/jbc.271.16.9422; RA Dias-Kadambi B.L., Drum C.L., Hanck D.A., Blumenthal K.M.; RT "Leucine 18, a hydrophobic residue essential for high affinity binding of RT anthopleurin B to the voltage-sensitive sodium channel."; RL J. Biol. Chem. 271:9422-9428(1996). RN [10] RP MUTAGENESIS OF TRP-33 AND TRP-45, AND SITES TRP-33 AND TRP-45. RX PubMed=8798612; DOI=10.1074/jbc.271.39.23828; RA Dias-Kadambi B.L., Combs K.A., Drum C.L., Hanck D.A., Blumenthal K.M.; RT "The role of exposed tryptophan residues in the activity of the cardiotonic RT polypeptide anthopleurin B."; RL J. Biol. Chem. 271:23828-23835(1996). RN [11] RP FUNCTION ON CHANNEL DOMAIN 1-DOMAIN 4 INTERFACE. RX PubMed=9306007; DOI=10.1007/s004240050460; RA Benzinger G.R., Drum C.L., Chen L.Q., Kallen R.G., Hanck D.A., Hanck D.; RT "Differences in the binding sites of two site-3 sodium channel toxins."; RL Pflugers Arch. 434:742-749(1997). RN [12] RP MUTAGENESIS OF LYS-37; HIS-39 AND TRP-45, AND SITES LYS-37; HIS-39 AND RP TRP-45. RX PubMed=9417050; DOI=10.1074/jbc.273.1.80; RA Benzinger G.R., Kyle J.W., Blumenthal K.M., Hanck D.A.; RT "A specific interaction between the cardiac sodium channel and site-3 toxin RT anthopleurin B."; RL J. Biol. Chem. 273:80-84(1998). RN [13] RP MUTAGENESIS OF GLY-10; GLY-15 AND GLY-20, AND SITES GLY-10; GLY-15 AND RP GLY-20. RX PubMed=14661964; DOI=10.1021/bi035291d; RA Seibert A.L., Liu J., Hanck D.A., Blumenthal K.M.; RT "Arg-14 loop of site 3 anemone toxins: effects of glycine replacement on RT toxin affinity."; RL Biochemistry 42:14515-14521(2003). RN [14] RP MUTAGENESIS OF ASN-16; THR-17 AND SER-19, AND SITES ASN-16; THR-17 AND RP SER-19. RX PubMed=15170345; DOI=10.1021/bi0496135; RA Seibert A.L., Liu J., Hanck D.A., Blumenthal K.M.; RT "Role of Asn-16 and Ser-19 in anthopleurin B binding. Implications for the RT electrostatic nature of Na(V) site 3."; RL Biochemistry 43:7082-7089(2004). RN [15] RP PHOSPHOLIPID-BINDING ACTIVITY. RX PubMed=15632158; DOI=10.1074/jbc.m412552200; RA Smith J.J., Alphy S., Seibert A.L., Blumenthal K.M.; RT "Differential phospholipid binding by site 3 and site 4 toxins. RT Implications for structural variability between voltage-sensitive sodium RT channel domains."; RL J. Biol. Chem. 280:11127-11133(2005). RN [16] RP FUNCTION. RX PubMed=24898004; DOI=10.1124/mol.114.092338; RA Xiao Y., Blumenthal K., Cummins T.R.; RT "Gating-pore currents demonstrate selective and specific modulation of RT individual sodium channel voltage-sensors by biological toxins."; RL Mol. Pharmacol. 86:159-167(2014). RN [17] RP REVIEW. RX PubMed=17092528; DOI=10.1016/j.toxicon.2006.09.017; RA Hanck D.A., Sheets M.F.; RT "Site-3 toxins and cardiac sodium channels."; RL Toxicon 49:181-193(2007). RN [18] RP NOMENCLATURE. RX PubMed=22683676; DOI=10.1016/j.toxicon.2012.05.020; RA Oliveira J.S., Fuentes-Silva D., King G.F.; RT "Development of a rational nomenclature for naming peptide and protein RT toxins from sea anemones."; RL Toxicon 60:539-550(2012). RN [19] RP STRUCTURE BY NMR, AND DISULFIDE BONDS. RX PubMed=7582896; DOI=10.1016/s0969-2126(01)00214-3; RA Monks S.A., Pallaghy P.K., Scanlon M.J., Norton R.S.; RT "Solution structure of the cardiostimulant polypeptide anthopleurin-B and RT comparison with anthopleurin-A."; RL Structure 3:791-803(1995). CC -!- FUNCTION: Binds specifically to voltage-gated sodium channels (Nav) CC (site 3), thereby delaying their inactivation. This toxin has the CC highest affinity of all anemone toxins for the mammalian sodium CC channel, whereas its paralog Anthopleurin-A retains the greatest CC capacity to discriminate between cardiac (Nav1.5/SCN5A) and neuronal CC sodium channels (PubMed:8916901). When tested electrophysiologically, CC this toxin exhibits a high affinity for multiple sodium channels with a CC 50-fold preference for rat cardiac (Nav1.5/SCN5A) over neuronal CC channels (0.1 nM versus 5 nM). When tested by ion flux, the affinities CC are similar and appear to have higher affinity (9 nM versus 22 nM) CC (PubMed:8276803, PubMed:7612595). The residue Lys-37 of this toxin has CC been shown to interact with channel Nav1.5 (residue Asp-1612 in rat and CC Asp-1610 in human), which is located in the DIV S3-S4 linker CC (corresponding to channel site 3) (PubMed:9417050, PubMed:24898004). CC Selectively modifies sodium channel inactivation from the open state CC with little effect on channel activation or on inactivation from closed CC states (By similarity). Does not display phospholipid-binding CC activities, suggesting that the domain IV S3-S4 linker is located at CC the extracellular surface and not buried in the phospholipid bilayer CC (PubMed:15632158). {ECO:0000250|UniProtKB:P01530, CC ECO:0000269|PubMed:15632158, ECO:0000269|PubMed:24898004, CC ECO:0000269|PubMed:7612595, ECO:0000269|PubMed:8276803, CC ECO:0000269|PubMed:8916901, ECO:0000269|PubMed:9306007, CC ECO:0000269|PubMed:9417050}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}. Nematocyst {ECO:0000305}. CC -!- SIMILARITY: Belongs to the sea anemone sodium channel inhibitory toxin CC family. Type I subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA27737.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; CC URL="https://en.wikipedia.org/wiki/Anthopleurin"; 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 EMBL; M90675; AAA27737.1; ALT_INIT; mRNA. DR PIR; A92547; NAXAB. DR PDB; 1APF; NMR; -; A=1-49. DR PDBsum; 1APF; -. DR AlphaFoldDB; P01531; -. DR SMR; P01531; -. DR EvolutionaryTrace; P01531; -. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0042151; C:nematocyst; IEA:UniProtKB-SubCell. DR GO; GO:0017080; F:sodium channel regulator activity; IEA:UniProtKB-KW. DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW. DR GO; GO:0009966; P:regulation of signal transduction; IEA:InterPro. DR Gene3D; 2.20.20.10; Anthopleurin-A; 1. DR InterPro; IPR000693; Anenome_toxin. DR InterPro; IPR023355; Myo_ane_neurotoxin_sf. DR Pfam; PF00706; Toxin_4; 1. DR PIRSF; PIRSF001905; Anenome_toxin; 1. DR SUPFAM; SSF57392; Defensin-like; 1. PE 1: Evidence at protein level; KW 3D-structure; Cardiotoxin; Direct protein sequencing; Disulfide bond; KW Ion channel impairing toxin; Nematocyst; Neurotoxin; Secreted; Toxin; KW Voltage-gated sodium channel impairing toxin. FT CHAIN 1..49 FT /note="Delta-actitoxin-Axm1b" FT /evidence="ECO:0000269|PubMed:4019448" FT /id="PRO_0000221516" FT REGION 1..7 FT /note="Well-structured region" FT /evidence="ECO:0000305|PubMed:14661964, FT ECO:0000305|PubMed:15170345" FT REGION 8..17 FT /note="Arg-14 loop (non-well-structured region)" FT /evidence="ECO:0000305|PubMed:14661964, FT ECO:0000305|PubMed:15170345" FT REGION 18..49 FT /note="Well-structured region" FT /evidence="ECO:0000305|PubMed:14661964, FT ECO:0000305|PubMed:15170345" FT SITE 7 FT /note="Structurally important" FT /evidence="ECO:0000305|PubMed:8639500" FT SITE 9 FT /note="Important for sodium channel affinity and for toxin FT structure" FT /evidence="ECO:0000305|PubMed:8639500" FT SITE 10 FT /note="Important for affinity to sodium channel, probably FT due to the flexibility this residue gives to the Arg-14 FT loop" FT /evidence="ECO:0000305|PubMed:14661964" FT SITE 12 FT /note="Key residue for binding both cardiac and neuronal FT sodium channels" FT /evidence="ECO:0000305|PubMed:8276803" FT SITE 13 FT /note="Important for sodium channel affinity" FT /evidence="ECO:0000305|PubMed:8916901" FT SITE 14 FT /note="Not essential for sodium channel affinity" FT /evidence="ECO:0000305|PubMed:8288644" FT SITE 15 FT /note="Important for affinity to sodium channel, probably FT due to the flexibility this residue gives to the Arg-14 FT loop" FT /evidence="ECO:0000305|PubMed:14661964" FT SITE 16 FT /note="Binds to sodium channel" FT /evidence="ECO:0000305|PubMed:15170345" FT SITE 17 FT /note="Has its side chain oriented away from the channel in FT the binary complex" FT /evidence="ECO:0000305|PubMed:15170345" FT SITE 18 FT /note="Important for high affinity to sodium channel" FT /evidence="ECO:0000305|PubMed:8621610" FT SITE 19 FT /note="Binds to sodium channel" FT /evidence="ECO:0000305|PubMed:15170345" FT SITE 20 FT /note="Structurally important" FT /evidence="ECO:0000305|PubMed:14661964" FT SITE 33 FT /note="Important for channel affinity" FT /evidence="ECO:0000305|PubMed:8798612" FT SITE 34 FT /note="Not important for channel affinity and toxin FT structure" FT /evidence="ECO:0000305|PubMed:8639500" FT SITE 37 FT /note="Important for channel affinity (interacts with rat FT Nav1.5 channel residue Asp-1612)" FT /evidence="ECO:0000305|PubMed:8639500, FT ECO:0000305|PubMed:9417050" FT SITE 39 FT /note="Not important for channel affinity and toxin FT structure" FT /evidence="ECO:0000305|PubMed:8639500" FT SITE 43 FT /note="Structurally important" FT /evidence="ECO:0000305|PubMed:8621610" FT SITE 45 FT /note="Does not affect binding, but may affect the FT stabilization of the cardiac channel open conformation" FT /evidence="ECO:0000305|PubMed:8798612" FT SITE 48 FT /note="Binds to sodium channel" FT /evidence="ECO:0000305|PubMed:8288644" FT SITE 49 FT /note="Important for most of the cardiac specificity" FT /evidence="ECO:0000305|PubMed:8276803" FT DISULFID 4..46 FT /evidence="ECO:0000269|PubMed:7582896" FT DISULFID 6..36 FT /evidence="ECO:0000269|PubMed:7582896" FT DISULFID 29..47 FT /evidence="ECO:0000269|PubMed:7582896" FT MUTAGEN 3 FT /note="P->S: Minor decrease in affinity for sodium channels FT (4.7-fold on neuronal and 2-fold on cardiac (Nav1.5) FT channels)." FT /evidence="ECO:0000269|PubMed:8916901" FT MUTAGEN 7 FT /note="D->A,N: Incorrect folding or very limited amount of FT mutant obtained." FT /evidence="ECO:0000269|PubMed:8639500" FT MUTAGEN 7 FT /note="D->K: Incorrect folding; when associated with D-37." FT /evidence="ECO:0000269|PubMed:8639500" FT MUTAGEN 7 FT /note="D->N: Small decrease in affinity (4-6-fold), and FT very limited amount of mutant obtained." FT /evidence="ECO:0000269|PubMed:8639500" FT MUTAGEN 9 FT /note="D->A: Major decrease in affinity for both cardiac FT (Nav1.5) (300-fold) and neuronal (100-fold) channels." FT /evidence="ECO:0000269|PubMed:8639500" FT MUTAGEN 9 FT /note="D->N: Decrease in affinity for both cardiac (Nav1.5) FT (10-fold) and neuronal (8-fold) channels." FT /evidence="ECO:0000269|PubMed:8639500" FT MUTAGEN 10 FT /note="G->A: Decrease in affinity for both cardiac (Nav1.5) FT (15-fold) and neuronal (450-fold) channels, as well as a FT 30-fold increase in discrimination for Nav1.5. Decrease in FT affinity for cardiac (Nav1.5) (600-fold); when associated FT with A-15. Not correctly folded; when associated with FT A-20." FT /evidence="ECO:0000269|PubMed:14661964" FT MUTAGEN 12 FT /note="R->A: Major decrease in affinity for both cardiac FT (Nav1.5) and neuronal sodium channels." FT /evidence="ECO:0000269|PubMed:8276803" FT MUTAGEN 12 FT /note="R->K: Minor effect on toxicity." FT /evidence="ECO:0000269|PubMed:8276803" FT MUTAGEN 12 FT /note="R->S: Minor effect on toxicity. Decrease in affinity FT for both cardiac (Nav1.5) (5-fold) and neuronal (37-fold) FT channels; when associated with Q-49 (tested by ion flux FT studies). Loss of discrimination between cardiac and FT neuronal channels; when associated with Val-13 and Q-49." FT /evidence="ECO:0000269|PubMed:7612595, FT ECO:0000269|PubMed:8276803, ECO:0000269|PubMed:8916901" FT MUTAGEN 13 FT /note="P->V: Decrease in affinity for both cardiac (Nav1.5) FT (9-fold) and neuronal channels (9-fold). Loss of FT discrimination between cardiac and neuronal channels; when FT associated with S-12 and Q-49." FT /evidence="ECO:0000269|PubMed:8916901" FT MUTAGEN 14 FT /note="R->A: Minor effect on toxicity." FT /evidence="ECO:0000269|PubMed:8288644" FT MUTAGEN 14 FT /note="R->K: Minor effect on toxicity." FT /evidence="ECO:0000269|PubMed:8288644" FT MUTAGEN 14 FT /note="R->Q: Minor effect on toxicity. Decrease in affinity FT for both cardiac (Nav1.5) (56-fold) and neuronal (72-fold) FT channels; when associated with S-12 (tested by ion flux FT studies). Decrease in affinity for both cardiac (Nav1.5) FT (13-fold) and neuronal (27-fold) channels; when associated FT with A-48 (tested by ion flux studies)." FT /evidence="ECO:0000269|PubMed:7612595, FT ECO:0000269|PubMed:8288644" FT MUTAGEN 15 FT /note="G->A: Decrease in affinity for both cardiac (Nav1.5) FT (13-fold) and neuronal (600-fold) channels, as well as a FT 50-fold increase in discrimination for Nav1.5. Decrease in FT affinity for cardiac (Nav1.5) (600-fold); when associated FT with A-10." FT /evidence="ECO:0000269|PubMed:14661964" FT MUTAGEN 16 FT /note="N->A: Decrease in affinity for cardiac (Nav1.5) FT (8-fold) channels." FT /evidence="ECO:0000269|PubMed:15170345" FT MUTAGEN 16 FT /note="N->D: Decrease in affinity for both cardiac (Nav1.5) FT (500-fold) and neuronal (3600-fold) channels." FT /evidence="ECO:0000269|PubMed:15170345" FT MUTAGEN 16 FT /note="N->R: Decrease in affinity for both cardiac (Nav1.5) FT (5-fold) and neuronal (56-fold) channels." FT /evidence="ECO:0000269|PubMed:15170345" FT MUTAGEN 17 FT /note="T->A,D: No change in activity." FT /evidence="ECO:0000269|PubMed:15170345" FT MUTAGEN 18 FT /note="L->A: Major decrease in affinity for both cardiac FT (Nav1.5) (330-fold) and neuronal (34-fold) channels, as FT well as a 9.5-fold decrease in discrimination for Nav1.5." FT /evidence="ECO:0000269|PubMed:8621610" FT MUTAGEN 18 FT /note="L->V: Decrease in affinity for both cardiac (Nav1.5) FT and neuronal channels." FT /evidence="ECO:0000269|PubMed:8621610" FT MUTAGEN 19 FT /note="S->A: Decrease in affinity for cardiac (Nav1.5) FT (5.6-fold) channels." FT /evidence="ECO:0000269|PubMed:15170345" FT MUTAGEN 19 FT /note="S->D: Major decrease in affinity for both cardiac FT (Nav1.5) (85-fold) and neuronal (653-fold) channels." FT /evidence="ECO:0000269|PubMed:15170345" FT MUTAGEN 19 FT /note="S->R: Decrease in affinity for both cardiac (Nav1.5) FT (5.7-fold) and neuronal (27-fold) channels." FT /evidence="ECO:0000269|PubMed:15170345" FT MUTAGEN 20 FT /note="G->A: Incorrect folding. Incorrect folding; when FT associated with A-10." FT /evidence="ECO:0000269|PubMed:14661964" FT MUTAGEN 21 FT /note="I->T: Minor decrease in affinity for sodium channels FT (2.2-fold on neuronal and 2.9-fold on cardiac (Nav1.5) FT channels)." FT /evidence="ECO:0000269|PubMed:8916901" FT MUTAGEN 24 FT /note="F->L: Minor decrease in affinity for sodium channels FT (4.8-fold on neuronal and 2.4-fold on cardiac (Nav1.5) FT channels)." FT /evidence="ECO:0000269|PubMed:8916901" FT MUTAGEN 33 FT /note="W->A: No mutant obtained." FT /evidence="ECO:0000269|PubMed:8798612" FT MUTAGEN 33 FT /note="W->F: Major decrease in affinity for both cardiac FT (Nav1.5) (31-fold) and neuronal (50-fold) channels (tested FT by ion flux studies). This mutant is the first ApB mutant FT that displays a significantly altered association rate FT (K(on))." FT /evidence="ECO:0000269|PubMed:8798612" FT MUTAGEN 33 FT /note="W->S: No mutant obtained." FT /evidence="ECO:0000269|PubMed:8798612" FT MUTAGEN 33 FT /note="W->Y: Minor decrease in affinity for both cardiac FT (Nav1.5) (5.6-fold) and neuronal (5-fold) channels." FT /evidence="ECO:0000269|PubMed:8798612" FT MUTAGEN 34 FT /note="H->A: Minor decrease in affinity." FT /evidence="ECO:0000269|PubMed:8639500" FT MUTAGEN 37 FT /note="K->A: Decrease in affinity for both cardiac (Nav1.5) FT (11-fold) and neuronal (7-fold) channels." FT /evidence="ECO:0000269|PubMed:8639500" FT MUTAGEN 37 FT /note="K->A: Decrease in affinity for cardiac (Nav1.5) FT channels (13-fold) (with decrease in K(on) and increase in FT K(off))." FT /evidence="ECO:0000269|PubMed:9417050" FT MUTAGEN 37 FT /note="K->D: Incorrect folding; when associated with K-7." FT /evidence="ECO:0000269|PubMed:8639500" FT MUTAGEN 39 FT /note="H->A: No change in activity." FT /evidence="ECO:0000269|PubMed:8639500" FT MUTAGEN 39 FT /note="H->A: Small decrease in affinity for cardiac FT (Nav1.5) channels (1.1-fold) (with increase in both K(on) FT and K(off))." FT /evidence="ECO:0000269|PubMed:9417050" FT MUTAGEN 42 FT /note="N->T: Minor decrease in affinity for sodium channels FT (1.1-fold on neuronal and 3.4-fold on cardiac (Nav1.5) FT channels)." FT /evidence="ECO:0000269|PubMed:8916901" FT MUTAGEN 43 FT /note="I->A,G,F: Incorrect folding." FT /evidence="ECO:0000269|PubMed:8621610" FT MUTAGEN 43 FT /note="I->L,V: Small decrease in apparent binding affinity FT for both neuronal and cardiac (Nav1.5) channels (tested by FT ion flux studies)." FT /evidence="ECO:0000269|PubMed:8621610" FT MUTAGEN 45 FT /note="W->A: Minor decrease in affinity for both cardiac FT (Nav1.5) (7.7-fold) and neuronal (4-fold) channels (tested FT by ion flux studies)." FT /evidence="ECO:0000269|PubMed:8798612" FT MUTAGEN 45 FT /note="W->F: Minor decrease in affinity for both cardiac FT (Nav1.5) (2-4-fold) (with decrease in K(on) and increase in FT K(off)) and neuronal (5-fold) channels (tested by ion flux FT studies)." FT /evidence="ECO:0000269|PubMed:8798612, FT ECO:0000269|PubMed:9417050" FT MUTAGEN 45 FT /note="W->S: Minor decrease in affinity for both cardiac FT (Nav1.5) (3.3-fold) and neuronal (7-fold) channels (tested FT by ion flux studies)." FT /evidence="ECO:0000269|PubMed:8798612" FT MUTAGEN 48 FT /note="K->A: Minor effect on toxicity. Decrease in affinity FT for both cardiac (Nav1.5) (13-fold) and neuronal (27-fold) FT channels; when associated with Q-14 (tested by ion flux FT studies)." FT /evidence="ECO:0000269|PubMed:7612595, FT ECO:0000269|PubMed:8288644" FT MUTAGEN 48 FT /note="K->Q: Minor effect on toxicity." FT /evidence="ECO:0000269|PubMed:8288644" FT MUTAGEN 48 FT /note="K->R: Minor effect on toxicity." FT /evidence="ECO:0000269|PubMed:8288644" FT MUTAGEN 49 FT /note="K->A: Minor effect on toxicity." FT /evidence="ECO:0000269|PubMed:8276803" FT MUTAGEN 49 FT /note="K->Q: Minor effect on toxicity. Decrease in affinity FT for both cardiac (Nav1.5) (5-fold) and neuronal (37-fold) FT channels; when associated with S-12 (tested by ion flux FT studies). Loss of discrimination between cardiac and FT neuronal channels; when associated with S-12 and V-13." FT /evidence="ECO:0000269|PubMed:7612595, FT ECO:0000269|PubMed:8276803, ECO:0000269|PubMed:8916901" FT MUTAGEN 49 FT /note="K->R: Minor effect on toxicity." FT /evidence="ECO:0000269|PubMed:8276803" FT CONFLICT 12..13 FT /note="RP -> PN (in Ref. 3; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 25 FT /note="Y -> A (in Ref. 3; AA sequence)" FT /evidence="ECO:0000305" FT TURN 14..17 FT /evidence="ECO:0007829|PDB:1APF" FT STRAND 20..23 FT /evidence="ECO:0007829|PDB:1APF" FT STRAND 42..47 FT /evidence="ECO:0007829|PDB:1APF" SQ SEQUENCE 49 AA; 5274 MW; 7BD237179065AE90 CRC64; GVPCLCDSDG PRPRGNTLSG ILWFYPSGCP SGWHNCKAHG PNIGWCCKK //