TXPR2_THRPR
ID TXPR2_THRPR Reviewed; 30 AA.
AC P83476;
DT 15-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 15-NOV-2002, sequence version 1.
DT 25-MAY-2022, entry version 77.
DE RecName: Full=Beta/omega-theraphotoxin-Tp2a {ECO:0000305};
DE Short=Beta/omega-TRTX-Tp2a {ECO:0000305};
DE AltName: Full=Protoxin-2 {ECO:0000305};
DE Short=ProTx-2 {ECO:0000305};
DE Short=ProTx2 {ECO:0000303|PubMed:30661758};
DE AltName: Full=Protoxin-II {ECO:0000303|PubMed:30661758};
DE Short=PT-II {ECO:0000303|PubMed:15632158};
DE Short=ProTx-II {ECO:0000303|PubMed:12475222, ECO:0000303|PubMed:15632158};
OS Thrixopelma pruriens (Peruvian green velvet tarantula).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Thrixopelma.
OX NCBI_TaxID=213387;
RN [1]
RP PROTEIN SEQUENCE, SYNTHESIS, FUNCTION, SUBCELLULAR LOCATION, MASS
RP SPECTROMETRY, AND DISULFIDE BONDS.
RC TISSUE=Venom;
RX PubMed=12475222; DOI=10.1021/bi026546a;
RA Middleton R.E., Warren V.A., Kraus R.L., Hwang J.C., Liu C.J., Dai G.,
RA Brochu R.M., Kohler M.G., Gao Y.-D., Garsky V.M., Bogusky M.J., Mehl J.T.,
RA Cohen C.J., Smith M.M.;
RT "Two tarantula peptides inhibit activation of multiple sodium channels.";
RL Biochemistry 41:14734-14747(2002).
RN [2]
RP FUNCTION.
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 [3]
RP FUNCTION.
RX PubMed=17339321; DOI=10.1074/jbc.m610462200;
RA Smith J.J., Cummins T.R., Alphy S., Blumenthal K.M.;
RT "Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5:
RT implied existence of a novel toxin binding site coupled to activation.";
RL J. Biol. Chem. 282:12687-12697(2007).
RN [4]
RP FUNCTION, SYNTHESIS, AND MUTAGENESIS OF TYR-1; GLN-3; TRP-5; MET-6; TRP-7;
RP THR-8; ASP-10; SER-11; GLU-12; LEU-23 AND TRP-24.
RX PubMed=17087985; DOI=10.1016/j.toxicon.2006.09.014;
RA Priest B.T., Blumenthal K.M., Smith J.J., Warren V.A., Smith M.M.;
RT "ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels.";
RL Toxicon 49:194-201(2007).
RN [5]
RP FUNCTION.
RX PubMed=18156314; DOI=10.1124/mol.107.041046;
RA Sokolov S., Kraus R.L., Scheuer T., Catterall W.A.;
RT "Inhibition of sodium channel gating by trapping the domain II voltage
RT sensor with protoxin II.";
RL Mol. Pharmacol. 73:1020-1028(2008).
RN [6]
RP FUNCTION.
RX PubMed=18728100; DOI=10.1124/mol.108.047670;
RA Schmalhofer W.A., Calhoun J., Burrows R., Bailey T., Kohler M.G.,
RA Weinglass A.B., Kaczorowski G.J., Garcia M.L., Koltzenburg M., Priest B.T.;
RT "ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action
RT potential propagation in nociceptors.";
RL Mol. Pharmacol. 74:1476-1484(2008).
RN [7]
RP FUNCTION.
RX PubMed=18657562; DOI=10.1016/j.toxicon.2008.06.023;
RA Edgerton G.B., Blumenthal K.M., Hanck D.A.;
RT "Evidence for multiple effects of ProTxII on activation gating in
RT Na(V)1.5.";
RL Toxicon 52:489-500(2008).
RN [8]
RP FUNCTION.
RX PubMed=20855463; DOI=10.1124/mol.110.066332;
RA Xiao Y., Blumenthal K., Jackson J.O. II, Liang S., Cummins T.R.;
RT "The tarantula toxins ProTx-II and huwentoxin-IV differentially interact
RT with human Nav1.7 voltage sensors to inhibit channel activation and
RT inactivation.";
RL Mol. Pharmacol. 78:1124-1134(2010).
RN [9]
RP FUNCTION ON CAV3.1 CALCIUM CHANNEL.
RX PubMed=20600227; DOI=10.1016/j.toxicon.2010.06.009;
RA Edgerton G.B., Blumenthal K.M., Hanck D.A.;
RT "Inhibition of the activation pathway of the T-type calcium channel
RT Ca(V)3.1 by ProTxII.";
RL Toxicon 56:624-636(2010).
RN [10]
RP FUNCTION.
RX PubMed=24297919; DOI=10.1073/pnas.1314557110;
RA Gilchrist J., Das S., Van Petegem F., Bosmans F.;
RT "Crystallographic insights into sodium-channel modulation by the beta4
RT subunit.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:E5016-E5024(2013).
RN [11]
RP FUNCTION.
RX PubMed=24886690; DOI=10.1186/1756-6606-7-36;
RA Bladen C., Hamid J., Souza I.A., Zamponi G.W.;
RT "Block of T-type calcium channels by protoxins I and II.";
RL Mol. Brain 7:36-36(2014).
RN [12]
RP DOMAIN.
RX PubMed=26843868; DOI=10.1155/2015/537508;
RA Kikuchi K., Sugiura M., Kimura T.;
RT "High proteolytic resistance of spider-derived inhibitor cystine knots.";
RL Int. J. Pept. 2015:537508-537508(2015).
RN [13]
RP FUNCTION.
RX PubMed=25658507; DOI=10.1021/jm501765v;
RA Murray J.K., Ligutti J., Liu D., Zou A., Poppe L., Li H., Andrews K.L.,
RA Moyer B.D., McDonough S.I., Favreau P., Stoecklin R., Miranda L.P.;
RT "Engineering potent and selective analogues of GpTx-1, a tarantula venom
RT peptide antagonist of the Na(V)1.7 sodium channel.";
RL J. Med. Chem. 58:2299-2314(2015).
RN [14]
RP FUNCTION.
RX PubMed=26894959; DOI=10.7554/elife.10960;
RA Das S., Gilchrist J., Bosmans F., Van Petegem F.;
RT "Binary architecture of the Nav1.2-beta2 signaling complex.";
RL Elife 5:0-0(2016).
RN [15]
RP PHARMACEUTICAL, AND MUTAGENESIS OF TYR-1; TRP-7 AND TRP-30.
RX PubMed=28045073; DOI=10.1038/srep39662;
RA Flinspach M., Xu Q., Piekarz A.D., Fellows R., Hagan R., Gibbs A., Liu Y.,
RA Neff R.A., Freedman J., Eckert W.A., Zhou M., Bonesteel R.,
RA Pennington M.W., Eddinger K.A., Yaksh T.L., Hunter M., Swanson R.V.,
RA Wickenden A.D.;
RT "Insensitivity to pain induced by a potent selective closed-state Nav1.7
RT inhibitor.";
RL Sci. Rep. 7:39662-39662(2017).
RN [16]
RP FUNCTION ON NAV1.7/SCN9A, AND SYNTHESIS.
RX PubMed=31234412; DOI=10.3390/toxins11060367;
RA Nicolas S., Zoukimian C., Bosmans F., Montnach J., Diochot S., Cuypers E.,
RA De Waard S., Beroud R., Mebs D., Craik D., Boturyn D., Lazdunski M.,
RA Tytgat J., De Waard M.;
RT "Chemical synthesis, proper folding, Nav channel selectivity profile and
RT analgesic properties of the spider peptide Phlotoxin 1.";
RL Toxins 11:0-0(2019).
RN [17]
RP STRUCTURE BY NMR, FUNCTION, AND MUTAGENESIS OF GLU-12 AND MET-19.
RX PubMed=25026046; DOI=10.1021/jm500687u;
RA Park J.H., Carlin K.P., Wu G., Ilyin V.I., Musza L.L., Blake P.R.,
RA Kyle D.J.;
RT "Studies examining the relationship between the chemical structure of
RT protoxin II and its activity on voltage gated sodium channels.";
RL J. Med. Chem. 57:6623-6631(2014).
RN [18] {ECO:0000312|PDB:2N9T}
RP STRUCTURE BY NMR, DISULFIDE BOND, SYNTHESIS, AND MUTAGENESIS OF LYS-4;
RP TRP-5; TRP-7; LYS-14; GLU-17; TRP-24; LYS-26; LYS-27; LYS-28 AND TRP-30.
RX PubMed=27311819; DOI=10.1074/jbc.m116.729095;
RA Henriques S.T., Deplazes E., Lawrence N., Cheneval O., Chaousis S.,
RA Inserra M., Thongyoo P., King G.F., Mark A.E., Vetter I., Craik D.J.,
RA Schroeder C.I.;
RT "Interaction of tarantula venom peptide ProTx-II with lipid membranes is a
RT prerequisite for its inhibition of human voltage-gated sodium channel
RT Nav1.7.";
RL J. Biol. Chem. 291:17049-17065(2016).
RN [19] {ECO:0000312|PDB:6N4I, ECO:0000312|PDB:6N4Q, ECO:0000312|PDB:6N4R}
RP X-RAY CRYSTALLOGRAPHY (3.54 ANGSTROMS) IN COMPLEX WITH VOLTAGE-SENSING
RP DOMAIN OF HUMAN NAV1.7 (SCN9A) IN A MEMBRANE-LIKE ENVIRONMENT, STRUCTURE BY
RP ELECTRON MICROSCOPY (3.60 ANGSTROMS), MUTAGENESIS OF ARG-22 AND LYS-26, AND
RP DISULFIDE BOND.
RX PubMed=30661758; DOI=10.1016/j.cell.2018.12.018;
RA Xu H., Li T., Rohou A., Arthur C.P., Tzakoniati F., Wong E., Estevez A.,
RA Kugel C., Franke Y., Chen J., Ciferri C., Hackos D.H., Koth C.M.,
RA Payandeh J.;
RT "Structural basis of Nav1.7 inhibition by a gating-modifier spider toxin.";
RL Cell 176:702-715(2019).
RN [20]
RP STRUCTURE BY ELECTRON MICROSCOPY (3.2 ANGSTROMS) IN COMPLEX WITH SCN9A;
RP SCN1B AND SCN2B, AND FUNCTION.
RX PubMed=30765606; DOI=10.1126/science.aaw2493;
RA Shen H., Liu D., Wu K., Lei J., Yan N.;
RT "Structures of human Nav1.7 channel in complex with auxiliary subunits and
RT animal toxins.";
RL Science 363:1303-1308(2019).
CC -!- FUNCTION: Gating-modifier toxin that targets voltage-gated sodium
CC channels with a selective activity on Nav1.7/SCN9A (IC(50)=1-1.5 nM)
CC (PubMed:25026046, PubMed:31234412). It inhibits both activation and
CC inactivation (PubMed:20855463). For inhibition of activation, it is
CC 100-fold more selective for Nav1.7/SCN9A (IC(50)=0.26-3) than for other
CC sodium channels (Nav1.2/SCN2A (IC(50)=40-540 nM), Nav1.3/SCN3A
CC (IC(50)=102 nM), Nav1.4/SCN4A (IC(50)=30-39 nM), Nav1.5/SCN5A
CC (IC(50)=19-90 nM), Nav1.6/SCN8A (IC(50)=26 nM), and Nav1.8/SCN10A
CC (IC(50)=146 nM)) (PubMed:12475222, PubMed:17087985, PubMed:18156314,
CC PubMed:18728100, PubMed:20855463, PubMed:25658507, PubMed:27311819,
CC PubMed:30661758). For inhibition of inactivation, it is 20-fold more
CC potent in inhibiting inactivation on Nav1.7/SCN9A (IC(50)=250 nM) than
CC other channels (about 4.6 uM for all channels) (PubMed:20855463). It
CC also weakly inhibits Cav1.2/CACNA1C and Cav3.2/CACNA1H (29% block at 1
CC uM) (PubMed:17087985, PubMed:20600227, PubMed:24886690). It inhibits
CC Nav1.7/SCN9A activation by interacting with DII and impairs
CC Nav1.7/SCN9A inactivation by interacting with DIV (PubMed:20855463). It
CC docks on top of the DII S3 helix Nav1.7/SCN9A (PubMed:30661758,
CC PubMed:30765606). It is about 60-fold less active on Nav1.7/SCN9A at
CC depolarized potential (0 mV; IC(50)=15 nM), compared to -120 mV
CC potential (IC(50)=0.26 nM) (PubMed:30661758). This toxin binds to lipid
CC membrane (PubMed:15632158, PubMed:27311819). This ability correlates
CC with hNav1.7/SCN9A inhibition, showing that membrane binding is the
CC first step in the inhibitory mechanism of this toxin (PubMed:27311819).
CC It inhibits Nav1.2/SCN2A less potently when it is coexpressed with
CC SCN2B or SCN4B than when it is expressed alone, showing that beta
CC subunits (SCN2B and SCN4B) have a protective effect (PubMed:24297919,
CC PubMed:26894959). {ECO:0000269|PubMed:12475222,
CC ECO:0000269|PubMed:15632158, ECO:0000269|PubMed:17087985,
CC ECO:0000269|PubMed:17339321, ECO:0000269|PubMed:18156314,
CC ECO:0000269|PubMed:18657562, ECO:0000269|PubMed:18728100,
CC ECO:0000269|PubMed:20855463, ECO:0000269|PubMed:24886690,
CC ECO:0000269|PubMed:25658507, ECO:0000269|PubMed:26894959,
CC ECO:0000269|PubMed:27311819, ECO:0000269|PubMed:30765606}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:12475222}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:12475222}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:27311819}.
CC -!- MASS SPECTROMETRY: Mass=3827; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:12475222};
CC -!- MASS SPECTROMETRY: Mass=3827; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:12475222};
CC -!- PHARMACEUTICAL: The derivative JNJ63955918 (Y1GPY; W7Q; W30L) is under
CC preclinical trial by Janssen Pharmaceutica as a non-opioid alternative
CC for the pharmacological treatment of severe pain.
CC {ECO:0000269|PubMed:28045073}.
CC -!- MISCELLANEOUS: The ability to inhibit Nav1.7/SCN9A is greatly enhances
CC by unatural modifications such as C-terminal amidation (5-fold) or C-
CC terminal addition of -NHCH3 (25-fold). Such modifications also improve
CC the ability to inhibit Nav1.2/SCN2A, but the selectivity for
CC Nav1.7/SCN9A over Nav1.2/SCN2A is retained.
CC {ECO:0000269|PubMed:25026046}.
CC -!- MISCELLANEOUS: Highly resistant to proteases, such as pepsin, trypsin,
CC chymotrypsin and elastase. The toxin is not degraded in the plasma and
CC shows fast clearance from the circulation.
CC {ECO:0000269|PubMed:26843868}.
CC -!- MISCELLANEOUS: Does not inhibit Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5,
CC and Kv2.1/KCNB1 channels (PubMed:12475222). Weakly inhibits calcium
CC channels hCav3.1/CACNA1G (9% inhibition at 1 uM or 81% at 5 uM) and
CC hCav3.3/CACNA1I (8.9% inhibition at 1 uM) (PubMed:24886690).
CC {ECO:0000269|PubMed:12475222, ECO:0000269|PubMed:24886690}.
CC -!- SIMILARITY: Belongs to the neurotoxin 30 (phrixotoxin) family.
CC {ECO:0000305}.
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DR PDB; 2N9T; NMR; -; A=1-30.
DR PDB; 5O0U; X-ray; 0.99 A; A=1-30.
DR PDB; 5TCZ; NMR; -; A=1-29.
DR PDB; 6MK4; NMR; -; A=1-30.
DR PDB; 6N4I; X-ray; 3.54 A; E/F/G/H=1-30.
DR PDB; 6N4Q; EM; 3.60 A; E/F/G/H=1-30.
DR PDB; 6N4R; EM; 4.20 A; E/F/G/H=1-30.
DR PDBsum; 2N9T; -.
DR PDBsum; 5O0U; -.
DR PDBsum; 5TCZ; -.
DR PDBsum; 6MK4; -.
DR PDBsum; 6N4I; -.
DR PDBsum; 6N4Q; -.
DR PDBsum; 6N4R; -.
DR AlphaFoldDB; P83476; -.
DR BMRB; P83476; -.
DR SMR; P83476; -.
DR TCDB; 8.B.5.2.1; the na(+)/k(+)/ca(2+) channel targeting tarantula huwentoxin (tht) family.
DR PRIDE; P83476; -.
DR ArachnoServer; AS000414; beta/omega-theraphotoxin-Tp2a.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005246; F:calcium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0017080; F:sodium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium channel impairing toxin; Direct protein sequencing;
KW Disulfide bond; Ion channel impairing toxin; Knottin; Lipid-binding;
KW Neurotoxin; Pharmaceutical; Secreted; Toxin;
KW Voltage-gated calcium channel impairing toxin;
KW Voltage-gated sodium channel impairing toxin.
FT PEPTIDE 1..30
FT /note="Beta/omega-theraphotoxin-Tp2a"
FT /evidence="ECO:0000269|PubMed:12475222"
FT /id="PRO_0000044556"
FT REGION 26..30
FT /note="Flexible tail region important for ability to
FT inhibit Nav channel"
FT /evidence="ECO:0000305|PubMed:25026046"
FT REGION 29..30
FT /note="Hydrophobic dyad that anchors the toxin into the
FT membrane while positioning it over the S3 helix of
FT Nav1.7/SCN9A"
FT /evidence="ECO:0000305|PubMed:30661758"
FT SITE 5
FT /note="Part of an aromatic-rich surface that anchors the
FT toxin toward the membrane core relative to lipid headgroups
FT bound along the pore module of Nav1.7/SCN9A"
FT /evidence="ECO:0000305|PubMed:30661758"
FT SITE 7
FT /note="Part of an aromatic-rich surface that anchors the
FT toxin toward the membrane core relative to lipid headgroups
FT bound along the pore module of Nav1.7/SCN9A"
FT /evidence="ECO:0000305|PubMed:30661758"
FT SITE 22
FT /note="Electrostatic gating-modifier of Nav1.7/SCN9A that
FT antagonizes outward gating-charge movement through direct
FT electrostatic repulsion; may also indirectly antagonize S4
FT gating-charge movement by neutralizing acidic side chains
FT within the extracellular vestibule of VSD2"
FT /evidence="ECO:0000305|PubMed:30661758"
FT SITE 24
FT /note="Part of an aromatic-rich surface that anchors the
FT toxin toward the membrane core relative to lipid headgroups
FT bound along the pore module of Nav1.7/SCN9A; it also
FT stabilizes the toxin for productive receptor site
FT engagement"
FT /evidence="ECO:0000305|PubMed:30661758"
FT SITE 26
FT /note="Antagonizes outward gating-charge movement of
FT Nav1.7/SCN9A through direct electrostatic repulsion; may
FT also indirectly antagonize S4 gating-charge movement by
FT neutralizing acidic side chains within the extracellular
FT vestibule of VSD2"
FT /evidence="ECO:0000305|PubMed:30661758"
FT SITE 30
FT /note="Part of an aromatic-rich surface that anchors the
FT toxin toward the membrane core relative to lipid headgroups
FT bound along the pore module of Nav1.7/SCN9A"
FT /evidence="ECO:0000305|PubMed:30661758"
FT DISULFID 2..16
FT /evidence="ECO:0000269|PubMed:12475222,
FT ECO:0000269|PubMed:27311819, ECO:0000269|PubMed:30661758,
FT ECO:0000312|PDB:2N9T, ECO:0000312|PDB:5O0U,
FT ECO:0000312|PDB:5TCZ, ECO:0000312|PDB:6N4I,
FT ECO:0000312|PDB:6N4Q, ECO:0000312|PDB:6N4R"
FT DISULFID 9..21
FT /evidence="ECO:0000269|PubMed:12475222,
FT ECO:0000269|PubMed:27311819, ECO:0000269|PubMed:30661758,
FT ECO:0000312|PDB:2N9T, ECO:0000312|PDB:5O0U,
FT ECO:0000312|PDB:5TCZ, ECO:0000312|PDB:6N4I,
FT ECO:0000312|PDB:6N4Q, ECO:0000312|PDB:6N4R"
FT DISULFID 15..25
FT /evidence="ECO:0000269|PubMed:12475222,
FT ECO:0000269|PubMed:27311819, ECO:0000269|PubMed:30661758,
FT ECO:0000312|PDB:2N9T, ECO:0000312|PDB:5O0U,
FT ECO:0000312|PDB:5TCZ, ECO:0000312|PDB:6N4I,
FT ECO:0000312|PDB:6N4Q, ECO:0000312|PDB:6N4R"
FT MUTAGEN 1
FT /note="Y->A: No change in binding affinity with
FT Nav1.5/SCN5A."
FT /evidence="ECO:0000269|PubMed:17087985"
FT MUTAGEN 1
FT /note="Y->GPY: Important increase in selectivity for
FT Nav1.7/SCN9A; derivative JNJ63955918."
FT /evidence="ECO:0000269|PubMed:28045073"
FT MUTAGEN 3
FT /note="Q->A: No change in binding affinity with
FT Nav1.5/SCN5A."
FT /evidence="ECO:0000269|PubMed:17087985"
FT MUTAGEN 4
FT /note="K->R: In K/R, 30-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and change in ability to bind membranes. In
FT K/R,E17K, 110-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and change in ability to bind membranes."
FT /evidence="ECO:0000269|PubMed:27311819"
FT MUTAGEN 5
FT /note="W->A: At least 10-fold decrease in affinity with
FT Nav1.5/SCN5A."
FT /evidence="ECO:0000269|PubMed:17087985"
FT MUTAGEN 5
FT /note="W->Y: 290-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and decrease in ability to bind membranes."
FT /evidence="ECO:0000269|PubMed:27311819"
FT MUTAGEN 6
FT /note="M->A: At least 10-fold decrease in affinity with
FT Nav1.5/SCN5A."
FT /evidence="ECO:0000269|PubMed:17087985"
FT MUTAGEN 7
FT /note="W->A: At least 10-fold decrease in affinity with
FT Nav1.5/SCN5A."
FT /evidence="ECO:0000269|PubMed:17087985"
FT MUTAGEN 7
FT /note="W->Q: Important increase in selectivity for
FT Nav1.7/SCN9A; derivative JNJ63955918."
FT /evidence="ECO:0000269|PubMed:28045073"
FT MUTAGEN 7
FT /note="W->Y: 111-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and decrease in ability to bind membranes."
FT /evidence="ECO:0000269|PubMed:27311819"
FT MUTAGEN 8
FT /note="T->A: No change in binding affinity with
FT Nav1.5/SCN5A."
FT /evidence="ECO:0000269|PubMed:17087985"
FT MUTAGEN 10
FT /note="D->A: No change in binding affinity with
FT Nav1.5/SCN5A."
FT /evidence="ECO:0000269|PubMed:17087985"
FT MUTAGEN 11
FT /note="S->A: No change in binding affinity with
FT Nav1.5/SCN5A."
FT /evidence="ECO:0000269|PubMed:17087985"
FT MUTAGEN 12
FT /note="E->A: No change in binding affinity with
FT Nav1.5/SCN5A. 5-fold increase in ability to inhibit sodium
FT channel Nav1.7/SCN9A. No change in activity towards
FT Nav1.7/SCN9A; when associated with L-19."
FT /evidence="ECO:0000269|PubMed:17087985,
FT ECO:0000269|PubMed:25026046"
FT MUTAGEN 14
FT /note="K->R: In K/R, 30-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and change in ability to bind membranes. In
FT K/R,E17K, 110-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and change in ability to bind membranes."
FT /evidence="ECO:0000269|PubMed:27311819"
FT MUTAGEN 17
FT /note="E->K: No change in ability to inhibit Nav1.7/SCN9A,
FT and change in ability to bind membranes. In K/R,E17K, 110-
FT fold decrease in ability to inhibit Nav1.7/SCN9A, and
FT change in ability to bind membranes."
FT /evidence="ECO:0000269|PubMed:27311819"
FT MUTAGEN 19
FT /note="M->L: 1.7-fold decrease in ability to inhibit sodium
FT channel Nav1.7/SCN9A. No change in activity towards
FT Nav1.7/SCN9A; when associated with A-12."
FT /evidence="ECO:0000269|PubMed:25026046"
FT MUTAGEN 22
FT /note="R->D,E: Important decrease in ability to inhibit
FT human Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 22
FT /note="R->K: Small decrease in ability to inhibit human
FT Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 22
FT /note="R->Q: Moderate decrease in ability to inhibit human
FT Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 23
FT /note="L->A: No change in binding affinity with
FT Nav1.5/SCN5A."
FT /evidence="ECO:0000269|PubMed:17087985"
FT MUTAGEN 24
FT /note="W->A: At least 10-fold decrease in affinity with
FT Nav1.5/SCN5A."
FT /evidence="ECO:0000269|PubMed:17087985"
FT MUTAGEN 24
FT /note="W->Y: 180-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and decrease in ability to bind membranes."
FT /evidence="ECO:0000269|PubMed:27311819"
FT MUTAGEN 26
FT /note="K->D: Important decrease in ability to inhibit human
FT Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 26
FT /note="K->E: Almost complete loss in ability to inhibit
FT human Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 26
FT /note="K->R: Small increase in ability to inhibit human
FT Nav1.7/SCN9A. In K/R, 30-fold decrease in ability to
FT inhibit Nav1.7/SCN9A, and change in ability to bind
FT membranes. In K/R,E17K, 110-fold decrease in ability to
FT inhibit Nav1.7/SCN9A, and change in ability to bind
FT membranes."
FT /evidence="ECO:0000269|PubMed:27311819,
FT ECO:0000269|PubMed:30661758"
FT MUTAGEN 27
FT /note="K->R: In K/R, 30-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and change in ability to bind membranes. In
FT K/R,E17K, 110-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and change in ability to bind membranes."
FT /evidence="ECO:0000269|PubMed:27311819"
FT MUTAGEN 28
FT /note="K->R: In K/R, 30-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and change in ability to bind membranes. In
FT K/R,E17K, 110-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and change in ability to bind membranes."
FT /evidence="ECO:0000269|PubMed:27311819"
FT MUTAGEN 30
FT /note="W->L: Important increase in selectivity for
FT Nav1.7/SCN9A; derivative JNJ63955918."
FT /evidence="ECO:0000269|PubMed:28045073"
FT MUTAGEN 30
FT /note="W->Y: 6-fold decrease in ability to inhibit
FT Nav1.7/SCN9A, and decrease in ability to bind membranes."
FT /evidence="ECO:0000269|PubMed:27311819"
FT STRAND 5..7
FT /evidence="ECO:0007829|PDB:2N9T"
FT STRAND 11..13
FT /evidence="ECO:0007829|PDB:5O0U"
FT TURN 16..18
FT /evidence="ECO:0007829|PDB:2N9T"
FT STRAND 19..27
FT /evidence="ECO:0007829|PDB:5O0U"
SQ SEQUENCE 30 AA; 3833 MW; 5B8CF4C6338C1B9B CRC64;
YCQKWMWTCD SERKCCEGMV CRLWCKKKLW
