3SI1A_DENAN
ID 3SI1A_DENAN Reviewed; 65 AA.
AC P85092; A0A1Z0YU62;
DT 03-NOV-2009, integrated into UniProtKB/Swiss-Prot.
DT 03-NOV-2009, sequence version 1.
DT 25-MAY-2022, entry version 39.
DE RecName: Full=Toxin AdTx1 {ECO:0000303|PubMed:20015090};
DE AltName: Full=Rho-elapitoxin-Da1a {ECO:0000305};
DE Short=Rho-Da1a {ECO:0000303|PubMed:21419153};
DE Short=Rho-EPTX-Da1a {ECO:0000305};
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, FUNCTION, SUBCELLULAR LOCATION, AND MASS SPECTROMETRY.
RC TISSUE=Venom;
RX PubMed=20015090; DOI=10.1111/j.1476-5381.2009.00532.x;
RA Quinton L., Girard E., Maiga A., Rekik M., Lluel P., Masuyer G.,
RA Larregola M., Marquer C., Ciolek J., Magnin T., Wagner R., Molgo J.,
RA Thai R., Fruchart-Gaillard C., Mourier G., Chamot-Rooke J., Menez A.,
RA Palea S., Servent D., Gilles N.;
RT "Isolation and pharmacological characterization of AdTx1, a natural peptide
RT displaying specific insurmountable antagonism of the alpha1A-
RT adrenoceptor.";
RL Br. J. Pharmacol. 159:316-325(2010).
RN [2]
RP PROTEIN SEQUENCE, FUNCTION, AND SYNTHESIS.
RX PubMed=21419153; DOI=10.1016/j.toxicon.2011.03.009;
RA Maiga A., Mourier G., Quinton L., Rouget C., Gales C., Denis C., Lluel P.,
RA Senard J.M., Palea S., Servent D., Gilles N.;
RT "G protein-coupled receptors, an unexploited animal toxin targets:
RT exploration of green mamba venom for novel drug candidates active against
RT adrenoceptors.";
RL Toxicon 59:487-496(2012).
RN [3]
RP FUNCTION, AND PHARMACEUTICAL.
RX PubMed=23005263; DOI=10.1111/j.1476-5381.2012.02231.x;
RA Palea S., Maiga A., Guilloteau V., Rekik M., Guerard M., Rouget C.,
RA Rischmann P., Botto H., Camparo P., Lluel P., Gilles N.;
RT "Effects of rho-Da1a a peptidic alpha(1) (A) -adrenoceptor antagonist in
RT human isolated prostatic adenoma and anaesthetized rats.";
RL Br. J. Pharmacol. 168:618-631(2013).
RN [4]
RP FUNCTION.
RX PubMed=23935897; DOI=10.1371/journal.pone.0068841;
RA Maiga A., Merlin J., Marcon E., Rouget C., Larregola M., Gilquin B.,
RA Fruchart-Gaillard C., Lajeunesse E., Marchetti C., Lorphelin A.,
RA Bellanger L., Summers R.J., Hutchinson D.S., Evans B.A., Servent D.,
RA Gilles N.;
RT "Orthosteric binding of rho-Da1a, a natural peptide of snake venom
RT interacting selectively with the alpha1A-adrenoceptor.";
RL PLoS ONE 8:E68841-E68841(2013).
RN [5]
RP SYNTHESIS.
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 [6]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS), SYNTHESIS, AND DISULFIDE BONDS.
RX PubMed=23722859; DOI=10.1107/s1744309113011470;
RA Maiga A., Vera L., Marchetti C., Lorphelin A., Bellanger L., Mourier G.,
RA Servent D., Gilles N., Stura E.A.;
RT "Crystallization of recombinant green mamba rho-Da1a toxin during a
RT lyophilization procedure and its structure determination.";
RL Acta Crystallogr. F 69:704-709(2013).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF MUTANT ANCTX1-W28R-I38S,
RP DISULFIDE BOND, AND MUTAGENESIS OF THR-5; ILE-12; ARG-28; VAL-31; ILE-35;
RP PRO-49; TYR-52; SER-54 AND LYS-59.
RX PubMed=28578406; DOI=10.1038/s41598-017-02953-0;
RA Blanchet G., Alili D., Protte A., Upert G., Gilles N., Tepshi L.,
RA Stura E.A., Mourier G., Servent D.;
RT "Ancestral protein resurrection and engineering opportunities of the mamba
RT aminergic toxins.";
RL Sci. Rep. 7:2701-2701(2017).
CC -!- FUNCTION: Orthosteric antagonist of the alpha-1A adrenergic receptor
CC (ADRA1A) with an affinity of 0.35 nM (PubMed:20015090). Has also
CC affinity for ADRA1B > ADRA2C > ADRA1D (PubMed:23935897). Acts as a
CC relaxant of smooth muscle. Reduces prostatic muscle tone as efficiently
CC as tamsulosin (an antagonist presently used), but with fewer
CC cardiovascular side effects (PubMed:23005263).
CC {ECO:0000269|PubMed:20015090, ECO:0000269|PubMed:21419153,
CC ECO:0000269|PubMed:23005263, ECO:0000269|PubMed:23935897}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:20015090}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:20015090}.
CC -!- MASS SPECTROMETRY: Mass=7278.3691; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:20015090};
CC -!- PHARMACEUTICAL: Due to its high selectivity and potent relaxing effect
CC on isolated prostate smooth muscle, this peptide is in the process of
CC therapeutic development.
CC -!- MISCELLANEOUS: Does not show interaction with adrenergic receptors
CC (ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2), dopaminergic receptors (DRD1,
CC DRD2, DRD3, DRD4, DRD5), histaminic receptors (HRH1, HRH3, HRH4),
CC muscarinic receptors (CHRM1, CHRM2, CHRM3, CHRM4, CHRM5), and
CC serotoninergic receptors (HTR1A, HTR2A, HTR2B, HTR2C, HTR5A, HTR6,
CC HTR7). {ECO:0000269|PubMed:23005263, ECO:0000269|PubMed:23935897,
CC ECO:0000269|PubMed:24793485}.
CC -!- MISCELLANEOUS: The mutant AncTx1-W28R-I38S (which is not mutated at
CC position 28 and 38) shows a 10-, 740- and 5-fold increase in inhibition
CC potency than the mutant AncTx1 on alpha-1A, alpha-1D and alpha-2C
CC adrenergic receptors, respectively, but is 2-fold less potent on alpha-
CC 1B adrenergic receptor. {ECO:0000269|PubMed:28578406}.
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}.
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DR PDB; 4IYE; X-ray; 1.95 A; A=1-65.
DR PDB; 5MG9; X-ray; 1.80 A; A=1-65.
DR PDBsum; 4IYE; -.
DR PDBsum; 5MG9; -.
DR AlphaFoldDB; P85092; -.
DR SMR; P85092; -.
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; Direct protein sequencing; Disulfide bond;
KW G-protein coupled receptor impairing toxin; Pharmaceutical; Secreted;
KW Toxin.
FT CHAIN 1..65
FT /note="Toxin AdTx1"
FT /evidence="ECO:0000269|PubMed:20015090,
FT ECO:0000269|PubMed:21419153"
FT /id="PRO_0000386623"
FT DISULFID 3..24
FT /evidence="ECO:0000269|PubMed:23722859,
FT ECO:0000312|PDB:4IYE"
FT DISULFID 17..42
FT /evidence="ECO:0000269|PubMed:23722859,
FT ECO:0000312|PDB:4IYE"
FT DISULFID 46..57
FT /evidence="ECO:0000269|PubMed:23722859,
FT ECO:0000312|PDB:4IYE"
FT DISULFID 58..63
FT /evidence="ECO:0000269|PubMed:23722859,
FT ECO:0000312|PDB:4IYE"
FT MUTAGEN 5
FT /note="T->K: In AncTx1; 2-4-fold increase in inhibition
FT potency on ADRA1A and ADRA1D adrenergic receptors and 17-
FT 20-fold decrease in inhibition potency on ADRA1B and ADRA2C
FT adrenergic receptors."
FT /evidence="ECO:0000269|PubMed:28578406"
FT MUTAGEN 12
FT /note="I->V: In AncTx1; 2-4-fold increase in inhibition
FT potency on ADRA1A and ADRA1D adrenergic receptors and 17-
FT 20-fold decrease in inhibition potency on ADRA1B and ADRA2C
FT adrenergic receptors."
FT /evidence="ECO:0000269|PubMed:28578406"
FT MUTAGEN 28
FT /note="R->W: In AncTx1; 2-4-fold increase in inhibition
FT potency on ADRA1A and ADRA1D adrenergic receptors and 17-
FT 20-fold decrease in inhibition potency on ADRA1B and ADRA2C
FT adrenergic receptors. In AncTx2; 2-3-fold decrease in
FT inhibition potency on ADRA1A, ADRA1B and ADRA2C adrenergic
FT receptors, and 15-fold increase in inhibition potency on
FT ADRA1D adrenergic receptor. In AncTx3; 2-3-fold decrease in
FT inhibition potency on ADRA1A, ADRA1B, and ADRA2C adrenergic
FT receptors, and 20-fold increase in inhibition potency on
FT ADRA1D adrenergic receptor."
FT /evidence="ECO:0000269|PubMed:28578406"
FT MUTAGEN 31
FT /note="V->I: In AncTx1; 2-4-fold increase in inhibition
FT potency on ADRA1A and ADRA1D adrenergic receptors and 17-
FT 20-fold decrease in inhibition potency on ADRA1B and ADRA2C
FT adrenergic receptors."
FT /evidence="ECO:0000269|PubMed:28578406"
FT MUTAGEN 35
FT /note="I->M: In AncTx1; 2-4-fold increase in inhibition
FT potency on ADRA1A and ADRA1D adrenergic receptors and 17-
FT 20-fold decrease in inhibition potency on ADRA1B and ADRA2C
FT adrenergic receptors."
FT /evidence="ECO:0000269|PubMed:28578406"
FT MUTAGEN 38
FT /note="S->I: In AncTx1; 2-4-fold increase in inhibition
FT potency on ADRA1A and ADRA1D adrenergic receptors and 17-
FT 20-fold decrease in inhibition potency on ADRA1B and ADRA2C
FT adrenergic receptors. In AncTx2; 2-3-fold decrease in
FT inhibition potency on ADRA1A, ADRA1B and ADRA2C adrenergic
FT receptors, and 15-fold increase in inhibition potency on
FT ADRA1D adrenergic receptor. In AncTx3; 2-3-fold decrease in
FT inhibition potency on ADRA1A, ADRA1B, and ADRA2C adrenergic
FT receptors, and 20-fold increase in inhibition potency on
FT ADRA1D adrenergic receptor. In AncTx4; no change in
FT inhibition potency on ADRA1A and ADRA2C adrenergic
FT receptors, and 2-3-fold increase in inhibition potency on
FT ADRA1B and ADRA1D adrenergic receptors."
FT /evidence="ECO:0000269|PubMed:28578406"
FT MUTAGEN 49
FT /note="P->A: In AncTx1; 2-4-fold increase in inhibition
FT potency on ADRA1A and ADRA1D adrenergic receptors and 17-
FT 20-fold decrease in inhibition potency on ADRA1B and ADRA2C
FT adrenergic receptors."
FT /evidence="ECO:0000269|PubMed:28578406"
FT MUTAGEN 52
FT /note="Y->R: In AncTx1; 2-4-fold increase in inhibition
FT potency on ADRA1A and ADRA1D adrenergic receptors and 17-
FT 20-fold decrease in inhibition potency on ADRA1B and ADRA2C
FT adrenergic receptors."
FT /evidence="ECO:0000269|PubMed:28578406"
FT MUTAGEN 54
FT /note="S->V: In AncTx1; 2-4-fold increase in inhibition
FT potency on ADRA1A and ADRA1D adrenergic receptors and 17-
FT 20-fold decrease in inhibition potency on ADRA1B and ADRA2C
FT adrenergic receptors."
FT /evidence="ECO:0000269|PubMed:28578406"
FT MUTAGEN 59
FT /note="K->G: In AncTx1; 2-4-fold increase in inhibition
FT potency on ADRA1A and ADRA1D adrenergic receptors and 17-
FT 20-fold decrease in inhibition potency on ADRA1B and ADRA2C
FT adrenergic receptors. In AncTx2; 2-3-fold decrease in
FT inhibition potency on ADRA1A, ADRA1B and ADRA2C adrenergic
FT receptors, and 15-fold increase in inhibition potency on
FT ADRA1D adrenergic receptor."
FT /evidence="ECO:0000269|PubMed:28578406"
FT STRAND 2..7
FT /evidence="ECO:0007829|PDB:5MG9"
FT STRAND 12..16
FT /evidence="ECO:0007829|PDB:5MG9"
FT STRAND 23..32
FT /evidence="ECO:0007829|PDB:5MG9"
FT STRAND 35..45
FT /evidence="ECO:0007829|PDB:5MG9"
FT STRAND 53..58
FT /evidence="ECO:0007829|PDB:5MG9"
FT TURN 61..64
FT /evidence="ECO:0007829|PDB:5MG9"
SQ SEQUENCE 65 AA; 7291 MW; 7EBB93826C586146 CRC64;
LTCVTSKSIF GITTEDCPDG QNLCFKRRHY VVPKIYDSTR GCAATCPIPE NYDSIHCCKT
DKCNE
