ID 3SIM1_DENAN Reviewed; 66 AA. AC P81030; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1997, sequence version 1. DT 24-JAN-2024, entry version 103. DE RecName: Full=Muscarinic toxin 1 {ECO:0000303|PubMed:8154745}; DE Short=MT1 {ECO:0000303|PubMed:8154745}; DE Short=MTx1 {ECO:0000303|PubMed:7778123}; 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 PROTEIN SEQUENCE, AND SUBCELLULAR LOCATION. RC TISSUE=Venom; RX PubMed=8154745; DOI=10.1111/j.1749-6632.1994.tb26623.x; RA Karlsson E., Jolkkonen M., Satyapan N., Adem A., Kumlin E., Hellman U., RA Wernstedt C.; RT "Protein toxins that bind to muscarinic acetylcholine receptors."; RL Ann. N. Y. Acad. Sci. 710:153-161(1994). RN [2] RP PROTEIN SEQUENCE, AND SUBCELLULAR LOCATION. RC TISSUE=Venom; RX PubMed=7570626; DOI=10.1016/0041-0101(94)00102-e; RA Jolkkonen M., Adem A., Hellman U., Wernstedt C., Karlsson E.; RT "A snake toxin against muscarinic acetylcholine receptors: amino acid RT sequence, subtype specificity and effect on guinea-pig ileum."; RL Toxicon 33:399-410(1995). RN [3] RP FUNCTION. RX PubMed=7778123; DOI=10.1016/0041-0101(94)00161-z; RA Kornisiuk E., Jerusalinsky D., Cervenansky C., Harvey A.L.; RT "Binding of muscarinic toxins MTx1 and MTx2 from the venom of the green RT mamba Dendroaspis angusticeps to cloned human muscarinic cholinoceptors."; RL Toxicon 33:11-18(1995). RN [4] RP SYNTHESIS, MUTAGENESIS OF ARG-34, AND FUNCTION. RC TISSUE=Venom; 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 [5] 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 [6] RP SYNTHESIS, AND FUNCTION. 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 [7] RP X-RAY CRYSTALLOGRAPHY (1.25 ANGSTROMS) OF 1-16 AND 49-57, SYNTHESIS, AND RP DISULFIDE BOND. 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). CC -!- FUNCTION: Shows a non-competitive interaction with adrenergic and CC muscarinic receptors. Binds to alpha-2b (ADRA2B) (IC(50)=2.3 nM), CC alpha-1a (ADRA1A), alpha-1b (ADRA1B), and alpha-2c (ADRA2C) adrenergic CC receptors. Reversibly binds to M1 (CHRM1) muscarinic acetylcholine CC receptors, probably by interacting with the orthosteric site CC (PubMed:7778123, PubMed:12488533, PubMed:24793485). Also reveals a CC slightly weaker effect at M3 (CHRM3) and M4 (CHRM4) receptors CC (PubMed:7778123, PubMed:12488533, PubMed:24793485). The order of CC potency is ADRA2B>>CHRM1>ADRA1A>ADRA1B>ADRA2C/CHRM4 (PubMed:24793485). CC {ECO:0000269|PubMed:12488533, ECO:0000269|PubMed:21557730, CC ECO:0000269|PubMed:24793485, ECO:0000269|PubMed:7778123}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:7570626, CC ECO:0000269|PubMed:8154745}. CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305}. CC -!- MISCELLANEOUS: Negative results: does not show interaction with CC adrenergic receptors (ADRA1D, ADRA2A, ADRB1, ADRB2), dopaminergic CC receptors (DRD1, DRD2, DRD3, DRD4, DRD5), histaminic receptors (HRH1, CC HRH3, HRH4) and serotoninergic receptors (HTR1A, HTR2A, HTR2B, HTR2C, CC HTR5A, HTR6, HTR7) (PubMed:21557730, PubMed:24793485). Does not show CC interaction with muscarinic receptors (CHRM2, CHRM3, CHRM5) CC (PubMed:7778123, 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 33 (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}. 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 PDB; 3FEV; X-ray; 1.30 A; A/B/C=1-16. DR PDB; 3NEQ; X-ray; 1.25 A; A/B=49-57. DR PDB; 4DO8; X-ray; 1.80 A; A/B=1-66. DR PDBsum; 3FEV; -. DR PDBsum; 3NEQ; -. DR PDBsum; 4DO8; -. DR AlphaFoldDB; P81030; -. DR SMR; P81030; -. DR TCDB; 1.C.74.1.6; the snake cytotoxin (sct) family. DR EvolutionaryTrace; P81030; -. 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; CD59; 1. DR InterPro; IPR003571; Snake_3FTx. DR InterPro; IPR045860; Snake_toxin-like_sf. DR InterPro; IPR018354; Snake_toxin_con_site. DR InterPro; IPR035076; Toxin/TOLIP. DR Pfam; PF00087; Toxin_TOLIP; 1. DR SUPFAM; SSF57302; Snake toxin-like; 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; Toxin. FT CHAIN 1..66 FT /note="Muscarinic toxin 1" FT /evidence="ECO:0000269|PubMed:7570626, FT ECO:0000269|PubMed:8154745" FT /id="PRO_0000093641" FT DISULFID 3..24 FT /evidence="ECO:0000269|PubMed:22720062, FT ECO:0000312|PDB:3FEV, ECO:0000312|PDB:3NEQ, FT ECO:0000312|PDB:4DO8" FT DISULFID 17..42 FT /evidence="ECO:0000269|PubMed:22720062, FT ECO:0000312|PDB:3FEV, ECO:0000312|PDB:3NEQ, FT ECO:0000312|PDB:4DO8" FT DISULFID 46..58 FT /evidence="ECO:0000269|PubMed:22720062, FT ECO:0000312|PDB:3FEV, ECO:0000312|PDB:3NEQ, FT ECO:0000312|PDB:4DO8" FT DISULFID 59..64 FT /evidence="ECO:0000269|PubMed:22720062, FT ECO:0000312|PDB:3FEV, ECO:0000312|PDB:3NEQ, FT ECO:0000312|PDB:4DO8" FT MUTAGEN 34 FT /note="R->A: Binds with 170-fold reduced affinity to M1 FT muscarinic acetylcholine receptors." FT /evidence="ECO:0000269|PubMed:12488533" FT STRAND 2..4 FT /evidence="ECO:0007829|PDB:3NEQ" FT STRAND 5..8 FT /evidence="ECO:0007829|PDB:3FEV" FT STRAND 11..16 FT /evidence="ECO:0007829|PDB:3FEV" FT STRAND 23..26 FT /evidence="ECO:0007829|PDB:3FEV" FT STRAND 35..45 FT /evidence="ECO:0007829|PDB:4DO8" FT STRAND 54..59 FT /evidence="ECO:0007829|PDB:3NEQ" FT TURN 62..65 FT /evidence="ECO:0007829|PDB:4DO8" SQ SEQUENCE 66 AA; 7518 MW; EAAC074F4A00DD3E CRC64; LTCVTSKSIF GITTENCPDG QNLCFKKWYY IVPRYSDITW GCAATCPKPT NVRETIRCCE TDKCNE //