3SX1_DENPO
ID 3SX1_DENPO Reviewed; 78 AA.
AC P0DKR6; B3EWQ5; K0C0K0;
DT 28-NOV-2012, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2012, sequence version 1.
DT 25-MAY-2022, entry version 38.
DE RecName: Full=Mambalgin-1 {ECO:0000303|PubMed:23034652};
DE Short=Mamb-1 {ECO:0000303|PubMed:23034652};
DE AltName: Full=Pi-Dp1 {ECO:0000303|PubMed:23034652};
DE Flags: Precursor;
OS Dendroaspis polylepis polylepis (Black mamba).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Elapidae; Elapinae; Dendroaspis.
OX NCBI_TaxID=8620;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 22-78, FUNCTION, BIOASSAY,
RP PHARMACEUTICAL, MASS SPECTROMETRY, 3D-STRUCTURE MODELING, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Venom, and Venom gland;
RX PubMed=23034652; DOI=10.1038/nature11494;
RA Diochot S., Baron A., Salinas M., Douguet D., Scarzello S.,
RA Dabert-Gay A.-S., Debayle D., Friend V., Alloui A., Lazdunski M.,
RA Lingueglia E.;
RT "Black mamba venom peptides target acid-sensing ion channels to abolish
RT pain.";
RL Nature 490:552-555(2012).
RN [2]
RP FUNCTION, AND REVIEW.
RX PubMed=23624383; DOI=10.1016/j.toxicon.2013.04.008;
RA Baron A., Diochot S., Salinas M., Deval E., Noel J., Lingueglia E.;
RT "Venom toxins in the exploration of molecular, physiological and
RT pathophysiological functions of acid-sensing ion channels.";
RL Toxicon 75:187-204(2013).
RN [3]
RP FUNCTION.
RX PubMed=25873388; DOI=10.1039/c5cc01418b;
RA Wen M., Guo X., Sun P., Xiao L., Li J., Xiong Y., Bao J., Xue T., Zhang L.,
RA Tian C.;
RT "Site-specific fluorescence spectrum detection and characterization of
RT hASIC1a channels upon toxin mambalgin-1 binding in live mammalian cells.";
RL Chem. Commun. (Camb.) 51:8153-8156(2015).
RN [4]
RP FUNCTION, AND BIOASSAY.
RX PubMed=26492527; DOI=10.1097/j.pain.0000000000000397;
RA Diochot S., Alloui A., Rodrigues P., Dauvois M., Friend V., Aissouni Y.,
RA Eschalier A., Lingueglia E., Baron A.;
RT "Analgesic effects of mambalgin peptide inhibitors of acid-sensing ion
RT channels in inflammatory and neuropathic pain.";
RL Pain 157:552-559(2016).
RN [5]
RP STRUCTURE BY NMR OF 22-78, FUNCTION, DISULFIDE BOND, AND SYNTHESIS OF
RP 22-78.
RX PubMed=24619065; DOI=10.1039/c4cc00779d;
RA Pan M., He Y., Wen M., Wu F., Sun D., Li S., Zhang L., Li Y., Tian C.;
RT "One-pot hydrazide-based native chemical ligation for efficient chemical
RT synthesis and structure determination of toxin Mambalgin-1.";
RL Chem. Commun. (Camb.) 50:5837-5839(2014).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 22-78, X-RAY CRYSTALLOGRAPHY (1.7
RP ANGSTROMS) OF MUTANT T44A, FUNCTION, SYNTHESIS OF 22-78, DISULFIDE BOND,
RP AND MUTAGENESIS OF HIS-42; THR-44; PHE-48; ARG-49; ASN-50; LEU-51; LYS-52;
RP LEU-53; ILE-54; LEU-55 AND LYS-78.
RX PubMed=26680001; DOI=10.1074/jbc.m115.702373;
RA Mourier G., Salinas M., Kessler P., Stura E.A., Leblanc M., Tepshi L.,
RA Besson T., Diochot S., Baron A., Douguet D., Lingueglia E., Servent D.;
RT "Mambalgin-1 pain-relieving peptide, stepwise solid-phase synthesis,
RT crystal structure, and functional domain for acid-sensing ion channel 1a
RT inhibition.";
RL J. Biol. Chem. 291:2616-2629(2016).
RN [7]
RP STRUCTURE BY ELECTRON MICROSCOPY (5.4 ANGSTROMS) OF 22-78 IN COMPLEX WITH
RP CHICKEN ASIC1A, SYNTHESIS OF 22-78, AND MUTAGENESIS OF GLN-26; HIS-27;
RP LYS-29; PHE-48 AND ARG-49.
RX PubMed=29872539; DOI=10.1038/s41421-018-0026-1;
RA Sun D., Yu Y., Xue X., Pan M., Wen M., Li S., Qu Q., Li X., Zhang L.,
RA Li X., Liu L., Yang M., Tian C.;
RT "Cryo-EM structure of the ASIC1a-mambalgin-1 complex reveals that the
RT peptide toxin mambalgin-1 inhibits acid-sensing ion channels through an
RT unusual allosteric effect.";
RL Cell Discov. 4:27-27(2018).
CC -!- FUNCTION: This three-finger toxin inhibits ASIC channels. It acts as a
CC gating modifier toxin by decreasing the apparent proton sensitivity of
CC activation and by slightly increasing the apparent proton sensitivity
CC for inactivation (PubMed:23034652). It binds more tightly to the closed
CC state and to a much lesser extent the inactivated/desensitized state of
CC ASIC1a isoform of ASIC1 (PubMed:23034652). It interacts directly with
CC the outside surface of the thumb domain of chicken ASIC1a (ASIC1a), but
CC does not insert into the acidic pocket as suggested for mambalgin-2
CC (PubMed:29872539). This binding leads to relocation of the thumb domain
CC that could disrupt the acidic pocket of cASIC1a (PubMed:29872539). It
CC reversibly inhibits rat ASIC1a (IC(50)=3.4-55 nM), rat ASIC1a-ASIC2b
CC (IC(50)=61 nM), rat ASIC1a-ASIC1b (IC(50)=72 nM), human ASIC1a
CC (IC(50)=127-580 nM), chicken ASIC1a (IC(50)=123.6 nM), rat ASIC1b
CC (IC(50)=22.2-203 nM), rat ASIC1a-ASIC2a (IC(50)=152-252 nM)
CC (PubMed:23034652, PubMed:23624383, PubMed:25873388, PubMed:24619065,
CC PubMed:26680001, PubMed:29872539). In vivo, it shows a potent naloxone-
CC resistant analgesic effect against acute and inflammatory pain upon
CC central and peripheral injection (PubMed:23034652). In addition, it
CC also has an opioid-independent effect on both thermal and mechanical
CC inflammatory pain after systemic administration and is effective
CC against neuropathic pain (PubMed:26680001).
CC {ECO:0000269|PubMed:23034652, ECO:0000269|PubMed:23624383,
CC ECO:0000269|PubMed:24619065, ECO:0000269|PubMed:26680001,
CC ECO:0000269|PubMed:29872539}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:23034652}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305}.
CC -!- MASS SPECTROMETRY: Mass=6555.7; Method=MALDI; Note=Average mass.;
CC Evidence={ECO:0000269|PubMed:23034652};
CC -!- PHARMACEUTICAL: Promising peptide that shows a potent analgesic effect
CC against acute and inflammatory pain that can be as strong as morphine
CC but resistant to naloxone, with much less tolerance and no respiratory
CC distress. {ECO:0000305|PubMed:23034652}.
CC -!- MISCELLANEOUS: Has no effect on rat ASIC2a, rat ASIC3, rat ASIC1a-ASIC3
CC and rat ASIC1b-ASIC3 channels, as well as on TRPV1, P2RX2 (P2X2), HTR3A
CC (5-HT3A), Nav1.8 (SCN10A), Cav3.2 (CACNA1H) and Kv1.2 (KCNA2) channels
CC (PubMed:23034652). Does not produce motor dysfunction, apathy, flaccid
CC paralysis, convulsions or death upon central injections (intrathecal or
CC intracerebroventricular) in mice (PubMed:23034652).
CC {ECO:0000269|PubMed:23034652}.
CC -!- SIMILARITY: Belongs to the snake three-finger toxin family. Short-chain
CC subfamily. Mambalgin sub-subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=The Electron Microscopy Data Bank;
CC URL="https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-6900";
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DR EMBL; JX428743; AFT65615.1; -; mRNA.
DR PDB; 2MJY; NMR; -; A=22-78.
DR PDB; 5DO6; X-ray; 1.70 A; A/B=22-78.
DR PDB; 5DU1; X-ray; 1.80 A; A/B/C/D=22-78.
DR PDB; 5DZ5; X-ray; 1.95 A; A/B=22-78.
DR PDB; 7CFT; EM; 3.90 A; D/E/F=22-78.
DR PDBsum; 2MJY; -.
DR PDBsum; 5DO6; -.
DR PDBsum; 5DU1; -.
DR PDBsum; 5DZ5; -.
DR PDBsum; 7CFT; -.
DR AlphaFoldDB; P0DKR6; -.
DR BMRB; P0DKR6; -.
DR SMR; P0DKR6; -.
DR TCDB; 8.B.23.1.1; the mambalgin (mambalgin) family.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0099106; F:ion channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR Gene3D; 2.10.60.10; -; 1.
DR InterPro; IPR045860; Snake_toxin-like_sf.
DR SUPFAM; SSF57302; SSF57302; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Pharmaceutical;
KW Proton-gated sodium channel impairing toxin; Secreted; Signal; Toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000269|PubMed:23034652"
FT CHAIN 22..78
FT /note="Mambalgin-1"
FT /evidence="ECO:0000269|PubMed:23034652"
FT /id="PRO_0000420360"
FT SITE 48
FT /note="Important residue for inhibition of rat ASIC1a"
FT /evidence="ECO:0000269|PubMed:26680001"
FT SITE 49
FT /note="Important residue for inhibition of rat ASIC1a"
FT /evidence="ECO:0000269|PubMed:26680001"
FT SITE 53
FT /note="Key residue for inhibition of rat ASIC1a, probably
FT binds to rat ASIC1a F-350"
FT /evidence="ECO:0000269|PubMed:26680001"
FT SITE 54
FT /note="Important residue for inhibition of rat ASIC1a"
FT /evidence="ECO:0000269|PubMed:26680001"
FT SITE 55
FT /note="Important residue for inhibition of rat ASIC1a"
FT /evidence="ECO:0000269|PubMed:26680001"
FT DISULFID 24..40
FT /evidence="ECO:0000269|PubMed:24619065,
FT ECO:0000269|PubMed:26680001, ECO:0000312|PDB:2MJY,
FT ECO:0000312|PDB:5DO6, ECO:0000312|PDB:5DU1,
FT ECO:0000312|PDB:5DZ5"
FT DISULFID 33..58
FT /evidence="ECO:0000269|PubMed:24619065,
FT ECO:0000269|PubMed:26680001, ECO:0000312|PDB:2MJY,
FT ECO:0000312|PDB:5DO6, ECO:0000312|PDB:5DU1,
FT ECO:0000312|PDB:5DZ5"
FT DISULFID 62..70
FT /evidence="ECO:0000269|PubMed:24619065,
FT ECO:0000269|PubMed:26680001, ECO:0000312|PDB:2MJY,
FT ECO:0000312|PDB:5DO6, ECO:0000312|PDB:5DU1,
FT ECO:0000312|PDB:5DZ5"
FT DISULFID 71..76
FT /evidence="ECO:0000269|PubMed:24619065,
FT ECO:0000269|PubMed:26680001, ECO:0000312|PDB:2MJY,
FT ECO:0000312|PDB:5DO6, ECO:0000312|PDB:5DU1,
FT ECO:0000312|PDB:5DZ5"
FT MUTAGEN 26
FT /note="Q->A: Small increase in inhibitory potency on
FT cASIC1a."
FT /evidence="ECO:0000269|PubMed:29872539"
FT MUTAGEN 27
FT /note="H->A: Important decrease in inhibitory potency on
FT cASIC1a."
FT /evidence="ECO:0000269|PubMed:29872539"
FT MUTAGEN 29
FT /note="K->A: No change in inhibitory potency on cASIC1a."
FT /evidence="ECO:0000269|PubMed:29872539"
FT MUTAGEN 42
FT /note="H->A: 3.1-fold decrease in inhibitory potency of
FT ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001"
FT MUTAGEN 44
FT /note="T->A: 3.9-fold decrease in inhibitory potency of
FT ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001"
FT MUTAGEN 48
FT /note="F->A: Important (34-fold) decrease in inhibitory
FT potency of ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001,
FT ECO:0000269|PubMed:29872539"
FT MUTAGEN 49
FT /note="R->A: Important (19-fold) decrease in inhibitory
FT potency of ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001,
FT ECO:0000269|PubMed:29872539"
FT MUTAGEN 50
FT /note="N->A: 2.8-fold decrease in inhibitory potency of
FT ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001"
FT MUTAGEN 51
FT /note="L->A: 5.1-fold decrease in inhibitory potency of
FT ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001"
FT MUTAGEN 52
FT /note="K->A: 4.9-fold decrease in inhibitory potency of
FT ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001"
FT MUTAGEN 53
FT /note="L->A: 2200-fold decrease in inhibitory potency of
FT ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001"
FT MUTAGEN 54
FT /note="I->A: 16.3-fold decrease in inhibitory potency of
FT ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001"
FT MUTAGEN 55
FT /note="L->A: 58-fold decrease in inhibitory potency of
FT ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001"
FT MUTAGEN 78
FT /note="K->A: 1.5-fold decrease in inhibitory potency of
FT ASIC1a."
FT /evidence="ECO:0000269|PubMed:26680001"
FT STRAND 23..26
FT /evidence="ECO:0007829|PDB:5DO6"
FT STRAND 29..32
FT /evidence="ECO:0007829|PDB:5DO6"
FT STRAND 39..48
FT /evidence="ECO:0007829|PDB:5DO6"
FT STRAND 51..60
FT /evidence="ECO:0007829|PDB:5DO6"
FT HELIX 64..69
FT /evidence="ECO:0007829|PDB:5DO6"
FT TURN 74..77
FT /evidence="ECO:0007829|PDB:5DO6"
SQ SEQUENCE 78 AA; 8853 MW; CC140CD5D3CB14FC CRC64;
MKTLLLTLLV VTIVCLDLGY SLKCYQHGKV VTCHRDMKFC YHNTGMPFRN LKLILQGCSS
SCSETENNKC CSTDRCNK
