ID   TXN1A_POERG             Reviewed;          28 AA.
AC   P0DUJ4;
DT   07-APR-2021, integrated into UniProtKB/Swiss-Prot.
DT   07-APR-2021, sequence version 1.
DT   25-MAY-2022, entry version 4.
DE   RecName: Full=NU-theraphotoxin-Preg1a {ECO:0000303|PubMed:32602722};
DE            Short=N-TRTX-Preg1a {ECO:0000303|PubMed:32602722};
DE            Short=NU-TRTX-Preg1a {ECO:0000303|PubMed:32602722};
OS   Poecilotheria regalis (Indian ornamental tree spider).
OC   Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC   Mygalomorphae; Theraphosidae; Poecilotheria.
OX   NCBI_TaxID=1203470;
RN   [1] {ECO:0007744|PDB:6SAA}
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SYNTHESIS, STRUCTURE BY NMR, AND
RP   DISULFIDE BONDS.
RC   TISSUE=Venom gland;
RX   PubMed=32602722; DOI=10.1021/acs.jmedchem.0c00485;
RA   Reynaud S., Ciolek J., Degueldre M., Saez N.J., Sequeira A.F., Duhoo Y.,
RA   Bras J.L.A., Meudal H., Cabo Diez M., Fernandez Pedrosa V., Verdenaud M.,
RA   Boeri J., Pereira Ramos O., Ducancel F., Vanden Driessche M., Fourmy R.,
RA   Violette A., Upert G., Mourier G., Beck-Sickinger A.G., Morl K., Landon C.,
RA   Fontes C.M.G.A., Minambres Herraiz R., Rodriguez de la Vega R.C.,
RA   Peigneur S., Tytgat J., Quinton L., De Pauw E., Vincentelli R., Servent D.,
RA   Gilles N.;
RT   "A venomics approach coupled to high-throughput toxin production strategies
RT   identifies the first venom-derived melanocortin receptor agonists.";
RL   J. Med. Chem. 63:8250-8264(2020).
CC   -!- FUNCTION: Toxin that acts as an agonist on melanocortin receptors
CC       (MC1R, MC3R, MC5R, MC5R). After binding to MC1R, the peptide activates
CC       the hMC1R/Gs pathway, but after binding to MC4R, it is not able to
CC       activate or antagonize the MC4R/Gs pathway. Inhibits melanocyte
CC       stimulating hormone (MSH)-binding to human receptors (Ki=1.8 uM to
CC       MC1R, Ki=19.8 uM to MC3R, Ki=7.1 uM to MC4R, Ki=10.0 uM to MC5R). This
CC       toxin is structurally unrelated to the natural agonists.
CC       {ECO:0000269|PubMed:32602722}.
CC   -!- FUNCTION: Toxin that acts as an agonist on melanocortin receptors
CC       (MC1R, MC3R, MC5R, MC5R). After binding to MC1R, the peptide activates
CC       the hMC1R/Gs pathway, but after binding to MC4R, it is not able to
CC       activate or antagonize the MC4R/Gs pathway. Inhibits melanocyte
CC       stimulating hormone (MSH)-binding to human receptors (Ki=2.9 uM to
CC       MC1R, Ki=3.9 uM to MC3R, Ki=2.6 uM to MC4R, Ki=2.2 uM to MC5R). This
CC       toxin is structurally unrelated to the natural agonists.
CC       {ECO:0000269|PubMed:32602722}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:32602722}.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC       {ECO:0000305|PubMed:32602722}.
CC   -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC       structurally defines this protein as a knottin.
CC       {ECO:0000305|PubMed:32602722}.
CC   -!- MISCELLANEOUS: Does not show activity when tested at 100 uM on
CC       mammalian sodium channels (Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5,
CC       Nav1.6, Nav1.7, and Nav1.8), potassium channels (Kv1.1, Kv1.2, Kv1.3,
CC       Kv1.4, Kv1.5, Kv1.6, Kv2.1, Kv3.1, Kv4.3, Kv7.1, Kv7.3, Kv10.1,
CC       Kv11.1(hERG), GIRK1), a calcium channel (Cav3.3), and nicotinic
CC       acetylcholine receceptors alpha1-beta-1-gamma-delta and nAChR alpha-7.
CC       {ECO:0000269|PubMed:32602722}.
CC   -!- MISCELLANEOUS: The letter 'N' in the name stands for the Greek letter
CC       'nu' that has been chosen as the activity descriptor for melanocortin
CC       receptor modulators. Since it is impossible to search for Greek letters
CC       in databases, the UniProt policy is to write all Greek letters as their
CC       full names (i.e. alpha, beta, etc.). {ECO:0000305|PubMed:32602722}.
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DR   PDB; 6SAA; NMR; -; A=1-28.
DR   PDBsum; 6SAA; -.
DR   AlphaFoldDB; P0DUJ4; -.
DR   SMR; P0DUJ4; -.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
PE   1: Evidence at protein level;
KW   3D-structure; Disulfide bond; G-protein coupled receptor impairing toxin;
KW   Knottin; Secreted; Toxin.
FT   PEPTIDE         1..28
FT                   /note="NU-theraphotoxin-Preg1a"
FT                   /evidence="ECO:0000269|PubMed:32602722"
FT                   /id="PRO_0000452480"
FT   DISULFID        2..19
FT                   /evidence="ECO:0000269|PubMed:32602722,
FT                   ECO:0007744|PDB:6SAA"
FT   DISULFID        9..22
FT                   /evidence="ECO:0000269|PubMed:32602722,
FT                   ECO:0007744|PDB:6SAA"
FT   DISULFID        18..27
FT                   /evidence="ECO:0000269|PubMed:32602722,
FT                   ECO:0007744|PDB:6SAA"
SQ   SEQUENCE   28 AA;  2922 MW;  FA1290235EF25975 CRC64;
     RCLHAGAACS GPIQKIPCCG TCSRRKCT