3NO2_NAJKA
ID 3NO2_NAJKA Reviewed; 86 AA.
AC P82935;
DT 01-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2010, sequence version 2.
DT 25-MAY-2022, entry version 84.
DE RecName: Full=Tryptophan-containing weak neurotoxin {ECO:0000303|PubMed:11223079};
DE Short=WTX {ECO:0000303|PubMed:15581687, ECO:0000303|PubMed:19377518, ECO:0000303|PubMed:19682302};
DE Flags: Precursor;
OS Naja kaouthia (Monocled cobra) (Naja siamensis).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Elapidae; Elapinae; Naja.
OX NCBI_TaxID=8649;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=12716062; DOI=10.1080/1521654021000061664;
RA Oustitch T.L., Peters L.E., Utkin Y.N., Tsetlin V.I.;
RT "Direct cloning of a target gene from a pool of homologous sequences:
RT complete cDNA sequence of a weak neurotoxin from cobra Naja kaouthia.";
RL IUBMB Life 55:43-47(2003).
RN [2]
RP PROTEIN SEQUENCE OF 22-86, MASS SPECTROMETRY, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=11223079; DOI=10.1016/s0041-0101(00)00223-3;
RA Utkin Y.N., Kukhtina V.V., Maslennikov I.V., Eletsky A.V., Starkov V.G.,
RA Weise C., Franke P., Hucho F., Tsetlin V.I.;
RT "First tryptophan-containing weak neurotoxin from cobra venom.";
RL Toxicon 39:921-927(2001).
RN [3]
RP PROTEIN SEQUENCE OF 22-37.
RC TISSUE=Venom;
RX PubMed=19377518; DOI=10.1134/s1068162009010026;
RA Starkov V.G., Polyak Y.L., Vulfius E.A., Kryukova E.V., Tsetlin V.I.,
RA Utkin Y.N.;
RT "New weak toxins from the cobra venom.";
RL Russ. J. Bioorg. Chem. 35:15-24(2009).
RN [4]
RP FUNCTION, AND MASS SPECTROMETRY.
RX PubMed=11279130; DOI=10.1074/jbc.m100788200;
RA Utkin Y.N., Kukhtina V.V., Kryukova E.V., Chiodini F., Bertrand D.,
RA Methfessel C., Tsetlin V.I.;
RT "'Weak toxin' from Naja kaouthia is a nontoxic antagonist of alpha-7 and
RT muscle-type nicotinic acetylcholine receptors.";
RL J. Biol. Chem. 276:15810-15815(2001).
RN [5]
RP FUNCTION.
RX PubMed=15581687; DOI=10.1016/j.toxicon.2004.09.014;
RA Ogay A.Y., Rzhevsky D.I., Murashev A.N., Tsetlin V.I., Utkin Y.N.;
RT "Weak neurotoxin from Naja kaouthia cobra venom affects haemodynamic
RT regulation by acting on acetylcholine receptors.";
RL Toxicon 45:93-99(2005).
RN [6]
RP FUNCTION, BIOASSAY, AND MASS SPECTROMETRY.
RC TISSUE=Venom;
RX PubMed=17371532; DOI=10.1111/j.1742-7843.2007.00045.x;
RA Mordvintsev D.Y., Rodionov D.I., Makarova M.V., Kamensky A.A.,
RA Levitskaya N.G., Ogay A.Y., Rzhevsky D.I., Murashev A.N., Tsetlin V.I.,
RA Utkin Y.N.;
RT "Behavioural effects in mice and intoxication symptomatology of weak
RT neurotoxin from cobra Naja kaouthia.";
RL Basic Clin. Pharmacol. Toxicol. 100:273-278(2007).
RN [7]
RP FUNCTION.
RX PubMed=19682302; DOI=10.1111/j.1742-4658.2009.07203.x;
RA Mordvintsev D.Y., Polyak Y.L., Rodionov D.I., Jakubik J., Dolezal V.,
RA Karlsson E., Tsetlin V.I., Utkin Y.N.;
RT "Weak toxin WTX from Naja kaouthia cobra venom interacts with both
RT nicotinic and muscarinic acetylcholine receptors.";
RL FEBS J. 276:5065-5075(2009).
RN [8]
RP FUNCTION.
RC TISSUE=Venom;
RX PubMed=26221036; DOI=10.1074/jbc.m115.648824;
RA Kudryavtsev D.S., Shelukhina I.V., Son L.V., Ojomoko L.O., Kryukova E.V.,
RA Lyukmanova E.N., Zhmak M.N., Dolgikh D.A., Ivanov I.A., Kasheverov I.E.,
RA Starkov V.G., Ramerstorfer J., Sieghart W., Tsetlin V.I., Utkin Y.N.;
RT "Neurotoxins from snake venoms and alpha-conotoxin ImI inhibit functionally
RT active ionotropic gamma-aminobutyric acid (GABA) receptors.";
RL J. Biol. Chem. 290:22747-22758(2015).
RN [9]
RP FUNCTION, MUTAGENESIS OF CYS-27; PRO-28; CYS-32; ARG-52; ARG-53; PRO-54;
RP TRP-57 AND ARG-58, RECOMBINANT EXPRESSION, AND 3D-STRUCTURE MODELING IN
RP COMPLEX WITH ALPHA-7/CHRNA7 NICOTINIC ACETYLCHOLINE RECEPTOR.
RX PubMed=27343701; DOI=10.1016/j.toxicon.2016.06.012;
RA Lyukmanova E.N., Shulepko M.A., Shenkarev Z.O., Kasheverov I.E.,
RA Chugunov A.O., Kulbatskii D.S., Myshkin M.Y., Utkin Y.N., Efremov R.G.,
RA Tsetlin V.I., Arseniev A.S., Kirpichnikov M.P., Dolgikh D.A.;
RT "Central loop of non-conventional toxin WTX from Naja kaouthia is important
RT for interaction with nicotinic acetylcholine receptors.";
RL Toxicon 119:274-279(2016).
RN [10]
RP STRUCTURE BY NMR OF 22-86 OF MUTANT ALA-54, DISULFIDE BOND, RECOMBINANT
RP EXPRESSION, AND 3D-STRUCTURE MODELING IN COMPLEX WITH M1 AND M3 MUSCARINIC
RP ACETYLCHOLINE RECEPTORS.
RX PubMed=26242733; DOI=10.1074/jbc.m115.656595;
RA Lyukmanova E.N., Shenkarev Z.O., Shulepko M.A., Paramonov A.S.,
RA Chugunov A.O., Janickova H., Dolejsi E., Dolezal V., Utkin Y.N.,
RA Tsetlin V.I., Arseniev A.S., Efremov R.G., Dolgikh D.A., Kirpichnikov M.P.;
RT "Structural insight into specificity of interactions between
RT nonconventional three-finger weak toxin from Naja kaouthia (WTX) and
RT muscarinic acetylcholine receptors.";
RL J. Biol. Chem. 290:23616-23630(2015).
CC -!- FUNCTION: Neurotoxin that irreversibly inhibits nicotinic acetylcholine
CC receptors (nAChR) and allosterically interacts with muscarinic
CC acetylcholine receptors (mAChR) (PubMed:11279130, PubMed:19682302). The
CC loop II is involved in the interaction of this toxin with nAChR and
CC mAChR (PubMed:27343701, PubMed:26242733). On nAChR, it acts as a
CC competitive antagonist (muscle-type and alpha-7/CHRNA7) with IC(50)
CC values in the micromolar range (PubMed:11279130, PubMed:27343701). On
CC mAChR, in presence of ACh, it partially inhibits the effect of
CC acetylcholine (ACh) (allosteric antagonist), whereas in the absence of
CC ACh, it activates the receptor (allosteric agonist) (PubMed:19682302).
CC It also shows a very weak inhibition of GABA(A) receptor composed of
CC alpha-1-beta-3-gamma-2 (GABRA1 AND GABRB3 AND GABRG2) subunits (10 uM
CC inhibit 31% current) (PubMed:26221036). In vivo, is nonlethal to mice
CC at concentrations up to 20 mg/kg, but exerts a myorelaxant effect,
CC induces a dose-dependent decrease in blood pressure and an increase in
CC heart rate in mice and rats (PubMed:15581687, PubMed:17371532).
CC {ECO:0000269|PubMed:11279130, ECO:0000269|PubMed:15581687,
CC ECO:0000269|PubMed:17371532, ECO:0000269|PubMed:19682302,
CC ECO:0000269|PubMed:26221036, ECO:0000269|PubMed:27343701}.
CC -!- SUBUNIT: Monomer in solution. {ECO:0000269|PubMed:26242733}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:11223079}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:11223079}.
CC -!- PTM: The disulfide bond Cys-27-Cys-32 is probably not needed for
CC efficient interaction of the toxin with the target receptor (Torpedo
CC muscle or alpha-7/CHRNA7 nAChR). {ECO:0000269|PubMed:27343701}.
CC -!- MASS SPECTROMETRY: Mass=7613; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:11223079, ECO:0000269|PubMed:11279130};
CC -!- MASS SPECTROMETRY: Mass=7615; Method=MALDI; Note=Average mass.;
CC Evidence={ECO:0000269|PubMed:17371532};
CC -!- MISCELLANEOUS: Exists in two form, due to cis-trans isomeriation of the
CC peptide bond 53-Arg-Pro-54. {ECO:0000269|PubMed:26242733}.
CC -!- SIMILARITY: Belongs to the snake three-finger toxin family. Ancestral
CC subfamily. Orphan group II sub-subfamily. {ECO:0000305}.
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DR PDB; 2MJ0; NMR; -; A=22-86.
DR PDBsum; 2MJ0; -.
DR AlphaFoldDB; P82935; -.
DR BMRB; P82935; -.
DR SMR; P82935; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR CDD; cd00206; snake_toxin; 1.
DR Gene3D; 2.10.60.10; -; 1.
DR InterPro; IPR003571; Snake_3FTx.
DR InterPro; IPR045860; Snake_toxin-like_sf.
DR InterPro; IPR018354; Snake_toxin_con_site.
DR SUPFAM; SSF57302; SSF57302; 1.
DR PROSITE; PS00272; SNAKE_TOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cardiotoxin; Direct protein sequencing; Disulfide bond;
KW G-protein coupled acetylcholine receptor impairing toxin;
KW G-protein coupled receptor impairing toxin; Neurotoxin;
KW Postsynaptic neurotoxin; Secreted; Signal; Toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000269|PubMed:11223079"
FT CHAIN 22..86
FT /note="Tryptophan-containing weak neurotoxin"
FT /evidence="ECO:0000269|PubMed:11223079"
FT /id="PRO_0000093632"
FT SITE 52
FT /note="Important for interaction with human M1/CHRM1 and
FT M3/CHRM3 mAChR, and muscle (Torpedo) and neuronal (alpha-
FT 7/CHRNA7) nAChR"
FT /evidence="ECO:0000269|PubMed:26242733,
FT ECO:0000269|PubMed:27343701"
FT SITE 53
FT /note="Important for interaction with human M1/CHRM1 and
FT M3/CHRM3 mAChR, and muscle (Torpedo) and neuronal (alpha-
FT 7/CHRNA7) nAChR"
FT /evidence="ECO:0000269|PubMed:26242733,
FT ECO:0000269|PubMed:27343701"
FT SITE 58
FT /note="Important for interaction with human M1/CHRM1 and
FT M3/CHRM3 mAChR, and only weakly for muscle (Torpedo) nAChR"
FT /evidence="ECO:0000269|PubMed:26242733,
FT ECO:0000269|PubMed:27343701"
FT DISULFID 24..45
FT /evidence="ECO:0000269|PubMed:26242733,
FT ECO:0000312|PDB:2MJ0"
FT DISULFID 27..32
FT /evidence="ECO:0000269|PubMed:26242733,
FT ECO:0000312|PDB:2MJ0"
FT DISULFID 38..63
FT /evidence="ECO:0000269|PubMed:26242733,
FT ECO:0000312|PDB:2MJ0"
FT DISULFID 67..78
FT /evidence="ECO:0000269|PubMed:26242733,
FT ECO:0000312|PDB:2MJ0"
FT DISULFID 79..84
FT /evidence="ECO:0000269|PubMed:26242733,
FT ECO:0000312|PDB:2MJ0"
FT MUTAGEN 27
FT /note="C->S: About 3-fold increase in inhibition potency
FT toward both muscle (Torpedo) and neuronal (alpha-7/CHRNA7)
FT nAChR; when associated with S-32."
FT /evidence="ECO:0000269|PubMed:27343701"
FT MUTAGEN 28
FT /note="P->A: No change in inhibition potency toward both
FT muscle (Torpedo) and neuronal (alpha-7/CHRNA7) nAChR."
FT /evidence="ECO:0000269|PubMed:27343701"
FT MUTAGEN 32
FT /note="C->S: About 3-fold increase in inhibition potency
FT toward both muscle (Torpedo) and neuronal (alpha-7/CHRNA7)
FT nAChR; when associated with S-27."
FT /evidence="ECO:0000269|PubMed:27343701"
FT MUTAGEN 52
FT /note="R->A: About 3.5-fold decrease in inhibition potency
FT toward both muscle (Torpedo) and neuronal (alpha-7/CHRNA7)
FT nAChR. About 4-fold decrease in inhibition potency toward
FT muscle (Torpedo) nAChR and complete loss of inhibition
FT potency toward neuronal (alpha-7/CHRNA7) nAChR; when
FT associated with A-53."
FT /evidence="ECO:0000269|PubMed:27343701"
FT MUTAGEN 53
FT /note="R->A: About 3-fold decrease in inhibition potency
FT toward muscle (Torpedo) nAChR and 5-fold decrease in
FT inhibition potency toward neuronal (alpha-7/CHRNA7) nAChR.
FT About 4-fold decrease in inhibition potency toward muscle
FT (Torpedo) nAChR and complete loss of inhibition potency
FT toward neuronal (alpha-7/CHRNA7) nAChR; when associated
FT with A-52."
FT /evidence="ECO:0000269|PubMed:27343701"
FT MUTAGEN 54
FT /note="P->A: Weak decrease in inhibition potency toward
FT muscle (Torpedo) and neuronal (alpha-7/CHRNA7) nAChR."
FT /evidence="ECO:0000269|PubMed:27343701"
FT MUTAGEN 57
FT /note="W->A: About 2.5-fold decrease in inhibition potency
FT toward muscle (Torpedo) nAChR and no change in inhibition
FT potency of neuronal (alpha-7/CHRNA7) nAChR."
FT /evidence="ECO:0000269|PubMed:27343701"
FT MUTAGEN 58
FT /note="R->A: Weak increase in inhibition potency toward
FT both muscle (Torpedo) and neuronal (alpha-7/CHRNA7) nAChR."
FT /evidence="ECO:0000269|PubMed:27343701"
FT STRAND 22..25
FT /evidence="ECO:0007829|PDB:2MJ0"
FT STRAND 28..31
FT /evidence="ECO:0007829|PDB:2MJ0"
FT STRAND 35..38
FT /evidence="ECO:0007829|PDB:2MJ0"
FT STRAND 44..50
FT /evidence="ECO:0007829|PDB:2MJ0"
FT HELIX 55..57
FT /evidence="ECO:0007829|PDB:2MJ0"
FT STRAND 59..66
FT /evidence="ECO:0007829|PDB:2MJ0"
FT STRAND 77..79
FT /evidence="ECO:0007829|PDB:2MJ0"
FT TURN 82..85
FT /evidence="ECO:0007829|PDB:2MJ0"
SQ SEQUENCE 86 AA; 9915 MW; FF92791A8794E7E3 CRC64;
MKTLLLTLVV VTIVCLDLGY TLTCLNCPEM FCGKFQICRN GEKICFKKLH QRRPLSWRYI
RGCADTCPVG KPYEMIECCS TDKCNR
