ID   3SX3_DENAN              Reviewed;          57 AA.
AC   C0HJB0;
DT   03-APR-2013, integrated into UniProtKB/Swiss-Prot.
DT   03-APR-2013, sequence version 1.
DT   25-MAY-2022, entry version 25.
DE   RecName: Full=Mambalgin-3 {ECO:0000303|Ref.1};
DE            Short=Mamb-3 {ECO:0000303|Ref.1};
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, MASS SPECTROMETRY, AND SUBCELLULAR LOCATION.
RC   TISSUE=Venom;
RA   Schweitz H., Diochot S., Baron A., Salinas M., Lingueglia E.;
RL   Submitted (FEB-2013) to UniProtKB.
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).
CC   -!- FUNCTION: This three-finger toxin inhibits ASIC channels (Ref.1). It
CC       acts as a gating modifier toxin by decreasing the apparent proton
CC       sensitivity of activation and by slightly increasing the apparent
CC       proton sensitivity for inactivation. It binds more tightly to the
CC       closed state and to a much lesser extent the inactivated/desensitized
CC       state of ASIC1a (By similarity). It interacts directly with the outside
CC       surface of the thumb domain of chicken ASIC1a (ASIC1a), but does not
CC       insert into the acidic pocket as suggested previously (By similarity).
CC       This binding leads to relocation of the thumb domain that could disrupt
CC       the acidic pocket of cASIC1a (By similarity). The peptide exerts both
CC       stimulatory and inhibitory effects on ASIC1a (By similarity). It
CC       reversibly inhibits rASIC1a (IC(50)=17 nM), rASIC1b (IC(50)= 44 nM) and
CC       rASIC1a-rASIC2a (IC(50)=252 nM) channels (Ref.1). In vivo, it shows a
CC       potent naloxone-resistant analgesic effect against acute and
CC       inflammatory pain upon central and peripheral injection. In addition,
CC       it also has an opioid-independent effect on both thermal and mechanical
CC       inflammatory pain after systemic administration and is effective
CC       against neuropathic pain (By similarity).
CC       {ECO:0000250|UniProtKB:P0DKR6, ECO:0000250|UniProtKB:P0DKS3,
CC       ECO:0000269|Ref.1}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|Ref.1}.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305|Ref.1}.
CC   -!- MASS SPECTROMETRY: Mass=6566.6; Mass_error=1; Method=MALDI;
CC       Evidence={ECO:0000269|Ref.1};
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:0000250|UniProtKB:P0DKR6}.
CC   -!- SIMILARITY: Belongs to the snake three-finger toxin family. Short-chain
CC       subfamily. Mambalgin sub-subfamily. {ECO:0000305}.
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DR   AlphaFoldDB; C0HJB0; -.
DR   BMRB; C0HJB0; -.
DR   SMR; C0HJB0; -.
DR   TCDB; 8.B.23.1.3; 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   Direct protein sequencing; Disulfide bond; Ion channel impairing toxin;
KW   Pharmaceutical; Proton-gated sodium channel impairing toxin; Secreted;
KW   Toxin.
FT   CHAIN           1..57
FT                   /note="Mambalgin-3"
FT                   /evidence="ECO:0000269|Ref.1"
FT                   /id="PRO_0000422048"
FT   DISULFID        3..19
FT                   /evidence="ECO:0000250|UniProtKB:B3EWH9"
FT   DISULFID        12..37
FT                   /evidence="ECO:0000250|UniProtKB:B3EWH9"
FT   DISULFID        41..49
FT                   /evidence="ECO:0000250|UniProtKB:B3EWH9"
FT   DISULFID        50..55
FT                   /evidence="ECO:0000250|UniProtKB:B3EWH9"
SQ   SEQUENCE   57 AA;  6575 MW;  EF5791129F09CED7 CRC64;
     LKCYQHGKVV TCHRDMKFCY HNIGMPFRNL KLILQGCSSS CSETENNKCC STDRCNK