3SIM7_DENAN
ID 3SIM7_DENAN Reviewed; 86 AA.
AC Q8QGR0; P80970; Q9PRZ5;
DT 23-MAY-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 25-MAY-2022, entry version 91.
DE RecName: Full=Muscarinic toxin 7 {ECO:0000303|PubMed:10799315, ECO:0000303|PubMed:32646996};
DE Short=MT-7;
DE Short=MT7 {ECO:0000303|PubMed:10799315, ECO:0000303|PubMed:32646996};
DE AltName: Full=Muscarinic toxin 1 {ECO:0000303|PubMed:8410188};
DE Short=m1-toxin {ECO:0000303|PubMed:8410188};
DE Flags: Precursor;
OS Dendroaspis angusticeps (Eastern green mamba) (Naja angusticeps).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Elapidae; Elapinae; Dendroaspis.
OX NCBI_TaxID=8618;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, MASS SPECTROMETRY, AND MUTAGENESIS OF
RP PHE-59 AND LYS-86.
RC TISSUE=Venom gland;
RX PubMed=11562434;
RA Krajewski J.L., Dickerson I.M., Potter L.T.;
RT "Site-directed mutagenesis of m1-toxin1: two amino acids responsible for
RT stable toxin binding to m1 muscarinic receptors.";
RL Mol. Pharmacol. 60:725-731(2001).
RN [2]
RP PROTEIN SEQUENCE OF 22-85, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=8410188; DOI=10.1523/jneurosci.13-10-04293.1993;
RA Max S.I., Liang J.-S., Potter L.T.;
RT "Purification and properties of m1-toxin, a specific antagonist of m1
RT muscarinic receptors.";
RL J. Neurosci. 13:4293-4300(1993).
RN [3]
RP PROTEIN SEQUENCE OF 22-86, AND FUNCTION.
RC TISSUE=Venom;
RX PubMed=10799315; DOI=10.1006/bbrc.2000.2657;
RA Naesman J., Jolkkonen M., Ammoun S., Karlsson E., Aakerman K.E.O.;
RT "Recombinant expression of a selective blocker of m1 muscarinic
RT receptors.";
RL Biochem. Biophys. Res. Commun. 271:435-439(2000).
RN [4]
RP PROTEIN SEQUENCE OF 22-86.
RC TISSUE=Venom;
RX PubMed=10665800; DOI=10.1016/s0041-0101(99)00141-5;
RA Carsi J.M., Potter L.T.;
RT "M1-toxin isotoxins from the green mamba (Dendroaspis angusticeps) that
RT selectively block m1 muscarinic receptors.";
RL Toxicon 38:187-198(2000).
RN [5]
RP SYNTHESIS OF 22-86, MUTAGENESIS OF ARG-55, AND FUNCTION.
RX PubMed=12488533; DOI=10.1124/mol.63.1.26;
RA Mourier G., Dutertre S., Fruchart-Gaillard C., Menez A., Servent D.;
RT "Chemical synthesis of MT1 and MT7 muscarinic toxins: critical role of Arg-
RT 34 in their interaction with M1 muscarinic receptor.";
RL Mol. Pharmacol. 63:26-35(2003).
RN [6]
RP FUNCTION.
RX PubMed=15033377; DOI=10.1016/j.ejphar.2004.01.029;
RA Olianas M.C., Adem A., Karlsson E., Onali P.;
RT "Action of the muscarinic toxin MT7 on agonist-bound muscarinic M1
RT receptors.";
RL Eur. J. Pharmacol. 487:65-72(2004).
RN [7]
RP FUNCTION.
RX PubMed=21557730; DOI=10.1111/j.1476-5381.2011.01468.x;
RA Naereoja K., Kukkonen J.P., Rondinelli S., Toivola D.M., Meriluoto J.,
RA Naesman J.;
RT "Adrenoceptor activity of muscarinic toxins identified from mamba venoms.";
RL Br. J. Pharmacol. 164:538-550(2011).
RN [8]
RP SYNTHESIS OF 22-86.
RX PubMed=24793485; DOI=10.1016/j.biochi.2014.04.009;
RA Blanchet G., Collet G., Mourier G., Gilles N., Fruchart-Gaillard C.,
RA Marcon E., Servent D.;
RT "Polypharmacology profiles and phylogenetic analysis of three-finger toxins
RT from mamba venom: case of aminergic toxins.";
RL Biochimie 103:109-117(2014).
RN [9] {ECO:0000312|PDB:2VLW}
RP X-RAY CRYSTALLOGRAPHY (1.39 ANGSTROMS) OF 22-86, AND DISULFIDE BONDS.
RX PubMed=18784346; DOI=10.1124/mol.108.050773;
RA Fruchart-Gaillard C., Mourier G., Marquer C., Stura E., Birdsall N.J.,
RA Servent D.;
RT "Different interactions between MT7 toxin and the human muscarinic M1
RT receptor in its free and N-methylscopolamine-occupied states.";
RL Mol. Pharmacol. 74:1554-1563(2008).
RN [10] {ECO:0000312|PDB:3FEV, ECO:0000312|PDB:3NEQ}
RP X-RAY CRYSTALLOGRAPHY (1.25 ANGSTROMS) OF 22-86.
RX PubMed=22720062; DOI=10.1371/journal.pone.0039166;
RA Fruchart-Gaillard C., Mourier G., Blanchet G., Vera L., Gilles N.,
RA Menez R., Marcon E., Stura E.A., Servent D.;
RT "Engineering of three-finger fold toxins creates ligands with original
RT pharmacological profiles for muscarinic and adrenergic receptors.";
RL PLoS ONE 7:E39166-E39166(2012).
RN [11] {ECO:0000312|PDB:6WJC}
RP X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) OF 22-86 IN COMPLEX WITH MUSCARINIC
RP ACETYLCHOLINE M1 RECEPTOR, DISULFIDE BONDS, AND MUTAGENESIS OF TRP-31;
RP GLU-36; 51-TYR--GLY-62 AND 71-GLU--VAL-75.
RX PubMed=32646996; DOI=10.1126/science.aax2517;
RA Maeda S., Xu J., Kadji F.M.N., Clark M.J., Zhao J., Tsutsumi N., Aoki J.,
RA Sunahara R.K., Inoue A., Garcia K.C., Kobilka B.K.;
RT "Structure and selectivity engineering of the M1 muscarinic receptor toxin
RT complex.";
RL Science 369:161-167(2020).
CC -!- FUNCTION: Binds specifically and irreversibly to an allosteric site of
CC the muscarinic acetylcholine M1 receptor (CHRM1) at subnanomolar
CC concentrations and shows a very slow dissociation rate
CC (PubMed:11562434, PubMed:10799315, PubMed:12488533, PubMed:21557730).
CC It also inhibits agonist-mediated guanosine 5'-O-(3'-thiotriphosphate)
CC (GTP-g-S) binding and downstream signaling, and decreases the
CC dissociation rate of orthosteric antagonists (N-methylscopolamine (NMS)
CC or pirenzepine) (PubMed:10799315, PubMed:15033377). Is a potent
CC negative allosteric modulator (NAM) for CHRM1 activation and a positive
CC allosteric modulator (PAM) for antagonist binding (Probable).
CC {ECO:0000269|PubMed:10799315, ECO:0000269|PubMed:11562434,
CC ECO:0000269|PubMed:12488533, ECO:0000269|PubMed:15033377,
CC ECO:0000269|PubMed:21557730, ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:8410188}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305}.
CC -!- DOMAIN: The finger loop 2 blocks access to the orthosteric site of the
CC muscarinic acetylcholine M1 receptor. Comparison of MT7 alone and MT7
CC in complex with CHRM1 shows that finger loops 1 and 3 undergo large
CC structural rearrangements upon binding to CHRM1, facilitating extensive
CC interactions with the receptor, while finger loop 2 is mostly
CC unchanged. {ECO:0000269|PubMed:32646996}.
CC -!- MASS SPECTROMETRY: Mass=7470.6; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:11562434};
CC -!- MISCELLANEOUS: Does not show interaction with adrenergic receptors
CC (ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2),
CC dopaminergic receptors (DRD1, DRD2, DRD3, DRD4, DRD5), histaminic
CC receptors (HRH1, HRH3, HRH4) and serotoninergic receptors (HTR1A,
CC HTR2A, HTR2B, HTR2C, HTR5A, HTR6, HTR7) (PubMed:21557730,
CC PubMed:24793485). Does not show interaction with muscarinic receptors
CC (CHRM2, CHRM3, CHRM4, CHRM5) (PubMed:12488533, PubMed:24793485).
CC {ECO:0000269|PubMed:12488533, ECO:0000269|PubMed:21557730,
CC ECO:0000269|PubMed:24793485}.
CC -!- MISCELLANEOUS: Is classified as a P-type cytotoxin, since a proline
CC residue stands at position 54 (Pro-31 in standard classification).
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the snake three-finger toxin family. Short-chain
CC subfamily. Aminergic toxin sub-subfamily.
CC {ECO:0000305|PubMed:24793485}.
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DR EMBL; AF241871; AAM00185.1; -; mRNA.
DR PDB; 2VLW; X-ray; 1.39 A; A/B=22-86.
DR PDB; 3FEV; X-ray; 1.30 A; A/B/C=38-86.
DR PDB; 3NEQ; X-ray; 1.25 A; A/B=22-69, A/B=78-86.
DR PDB; 6WJC; X-ray; 2.55 A; C=22-86.
DR PDBsum; 2VLW; -.
DR PDBsum; 3FEV; -.
DR PDBsum; 3NEQ; -.
DR PDBsum; 6WJC; -.
DR AlphaFoldDB; Q8QGR0; -.
DR SMR; Q8QGR0; -.
DR TCDB; 1.C.74.1.8; the snake cytotoxin (sct) family.
DR EvolutionaryTrace; Q8QGR0; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0048019; F:receptor antagonist activity; IDA:UniProtKB.
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; 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:10665800,
FT ECO:0000269|PubMed:10799315, ECO:0000269|PubMed:8410188"
FT CHAIN 22..86
FT /note="Muscarinic toxin 7"
FT /evidence="ECO:0000269|PubMed:10665800,
FT ECO:0000269|PubMed:10799315, ECO:0000269|PubMed:8410188"
FT /id="PRO_0000035481"
FT REGION 23..37
FT /note="Finger loop 1"
FT /evidence="ECO:0000305|PubMed:32646996"
FT REGION 44..63
FT /note="Finger loop 2"
FT /evidence="ECO:0000305|PubMed:32646996"
FT REGION 66..78
FT /note="Finger loop 3"
FT /evidence="ECO:0000305|PubMed:32646996"
FT DISULFID 24..45
FT /evidence="ECO:0000269|PubMed:18784346,
FT ECO:0000269|PubMed:22720062, ECO:0000269|PubMed:32646996,
FT ECO:0007744|PDB:2VLW, ECO:0007744|PDB:3FEV,
FT ECO:0007744|PDB:3NEQ, ECO:0007744|PDB:6WJC"
FT DISULFID 38..63
FT /evidence="ECO:0000269|PubMed:18784346,
FT ECO:0000269|PubMed:22720062, ECO:0000269|PubMed:32646996,
FT ECO:0007744|PDB:2VLW, ECO:0007744|PDB:3FEV,
FT ECO:0007744|PDB:3NEQ, ECO:0007744|PDB:6WJC"
FT DISULFID 67..78
FT /evidence="ECO:0000269|PubMed:18784346,
FT ECO:0000269|PubMed:22720062, ECO:0000269|PubMed:32646996,
FT ECO:0007744|PDB:2VLW, ECO:0007744|PDB:3FEV,
FT ECO:0007744|PDB:3NEQ, ECO:0007744|PDB:6WJC"
FT DISULFID 79..84
FT /evidence="ECO:0000269|PubMed:18784346,
FT ECO:0000269|PubMed:22720062, ECO:0000269|PubMed:32646996,
FT ECO:0007744|PDB:2VLW, ECO:0007744|PDB:3FEV,
FT ECO:0007744|PDB:3NEQ, ECO:0007744|PDB:6WJC"
FT MUTAGEN 31
FT /note="W->R: In Tx24; change in selectivity from CHRM1 to
FT CHRM2."
FT /evidence="ECO:0000269|PubMed:32646996"
FT MUTAGEN 36
FT /note="E->G: In Tx24; change in selectivity from CHRM1 to
FT CHRM2."
FT /evidence="ECO:0000269|PubMed:32646996"
FT MUTAGEN 51..62
FT /note="YISPRMYDFTRG->SPGMPRPMWALV: In Tx24; change in
FT selectivity from CHRM1 to CHRM2."
FT /evidence="ECO:0000269|PubMed:32646996"
FT MUTAGEN 55
FT /note="R->A: 105-fold decrease in affinity to CHRM1 and
FT change from irreversible to reversible binding."
FT /evidence="ECO:0000269|PubMed:12488533"
FT MUTAGEN 59
FT /note="F->I: Decrease in affinity to CHRM1 and change from
FT irreversible to reversible binding."
FT /evidence="ECO:0000269|PubMed:11562434"
FT MUTAGEN 71..75
FT /note="EYRDV->PPNED: In Tx24; change in selectivity from
FT CHRM1 to CHRM2."
FT /evidence="ECO:0000269|PubMed:32646996"
FT MUTAGEN 86
FT /note="K->E: Decrease in affinity to M1 muscarinic
FT acetylcholine receptors."
FT /evidence="ECO:0000269|PubMed:11562434"
FT CONFLICT 49..50
FT /note="WQ -> HW (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT STRAND 23..27
FT /evidence="ECO:0007829|PDB:3NEQ"
FT STRAND 29..31
FT /evidence="ECO:0007829|PDB:3NEQ"
FT STRAND 34..37
FT /evidence="ECO:0007829|PDB:3NEQ"
FT STRAND 44..53
FT /evidence="ECO:0007829|PDB:3NEQ"
FT STRAND 56..66
FT /evidence="ECO:0007829|PDB:3NEQ"
FT STRAND 75..79
FT /evidence="ECO:0007829|PDB:3FEV"
FT TURN 82..85
FT /evidence="ECO:0007829|PDB:3NEQ"
SQ SEQUENCE 86 AA; 9771 MW; 3AA85611258E5B9C CRC64;
MKTLLLTLVV VTIVCLDLGY TLTCVKSNSI WFPTSEDCPD GQNLCFKRWQ YISPRMYDFT
RGCAATCPKA EYRDVINCCG TDKCNK
