3SX2_DENPO
ID 3SX2_DENPO Reviewed; 57 AA.
AC P0DKS3; B3EWQ4;
DT 28-NOV-2012, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2012, sequence version 1.
DT 25-MAY-2022, entry version 34.
DE RecName: Full=Mambalgin-2 {ECO:0000303|PubMed:23034652};
DE Short=Ma-2 {ECO:0000303|PubMed:24323786};
DE Short=Mamb-2 {ECO:0000303|PubMed:23034652};
DE AltName: Full=Pi-Dp2 {ECO:0000303|PubMed:23034652};
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 PROTEIN SEQUENCE, MASS SPECTROMETRY, PHARMACEUTICAL, FUNCTION, AND
RP SUBCELLULAR LOCATION.
RC TISSUE=Venom;
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=24695733; DOI=10.1074/jbc.m114.561076;
RA Salinas M., Besson T., Delettre Q., Diochot S., Boulakirba S., Douguet D.,
RA Lingueglia E.;
RT "Binding site and inhibitory mechanism of the mambalgin-2 pain-relieving
RT peptide on acid-sensing ion channel 1a.";
RL J. Biol. Chem. 289:13363-13373(2014).
RN [4]
RP FUNCTION, AND SYNTHESIS.
RX PubMed=26991634; DOI=10.1002/psc.2868;
RA Lan H., Wu K., Zheng Y., Pan M., Huang Y.C., Gao S., Zheng Q.Y.,
RA Zheng J.S., Li Y.M., Xiao B., Liu L.;
RT "Total synthesis of mambalgin-1/2/3 by two-segment hydrazide-based native
RT chemical ligation.";
RL J. Pept. Sci. 22:320-326(2016).
RN [5]
RP STRUCTURE BY NMR, SYNTHESIS, AND DISULFIDE BONDS.
RX PubMed=24323786; DOI=10.1002/anie.201308898;
RA Schroeder C.I., Rash L.D., Vila-Farres X., Rosengren K.J., Mobli M.,
RA King G.F., Alewood P.F., Craik D.J., Durek T.;
RT "Chemical synthesis, 3D structure, and ASIC binding site of the toxin
RT mambalgin-2.";
RL Angew. Chem. Int. Ed. 53:1017-1020(2014).
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:24695733). 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:24695733). 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 previously (By
CC similarity). This binding leads to relocation of the thumb domain that
CC could disrupt the acidic pocket of cASIC1a (By similarity). The peptide
CC exerts both stimulatory and inhibitory effects on ASIC1a
CC (PubMed:24695733). It reversibly inhibits rat ASIC1a (IC(50)=21-55 nM),
CC rat ASIC1b (IC(50)=103-192 nM), rat ASIC1a-ASIC1b (IC(50)=72 nM), rat
CC ASIC1a-ASIC2a (IC(50)=246-252 nM) and rat ASIC1a-ASIC2b (IC(50)=61 nM)
CC (PubMed:23034652, PubMed:23624383, PubMed:24323786, PubMed:24695733,
CC PubMed:26991634). In vivo, it shows a potent naloxone-resistant
CC analgesic effect against acute and inflammatory pain upon central and
CC peripheral injection (By similarity). In addition, it also has an
CC opioid-independent effect on both thermal and mechanical inflammatory
CC pain after systemic administration and is effective against neuropathic
CC pain (By similarity). {ECO:0000250|UniProtKB:P0DKR6,
CC ECO:0000269|PubMed:23034652, ECO:0000269|PubMed:23624383,
CC ECO:0000269|PubMed:24323786, ECO:0000269|PubMed:24695733,
CC ECO:0000269|PubMed:26991634}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:23034652}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305}.
CC -!- MASS SPECTROMETRY: Mass=6538.4; Method=MALDI;
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:0000250|UniProtKB:P0DKR6}.
CC -!- MISCELLANEOUS: Has no effect on rat ASIC2a (PubMed:24695733). Has no
CC effect on rat ASIC3, rat ASIC1a-ASIC3 and rat ASIC1b-ASIC3 channels, as
CC well as on TRPV1, P2RX2 (P2X2), HTR3A (5-HT3A), Nav1.8 (SCN10A), Cav3.2
CC (CACNA1H) and Kv1.2 (KCNA2) channels (By similarity). Does not produce
CC motor dysfunction, apathy, flaccid paralysis, convulsions or death upon
CC central injections (intrathecal or intracerebroventricular) in mice (By
CC similarity). {ECO:0000250|UniProtKB:P0DKR6,
CC ECO:0000269|PubMed:24695733}.
CC -!- SIMILARITY: Belongs to the snake three-finger toxin family. Short-chain
CC subfamily. Mambalgin sub-subfamily. {ECO:0000305}.
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DR PDB; 2MFA; NMR; -; A=1-57.
DR PDBsum; 2MFA; -.
DR AlphaFoldDB; P0DKS3; -.
DR BMRB; P0DKS3; -.
DR SMR; P0DKS3; -.
DR TCDB; 8.B.23.1.2; 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; Toxin.
FT CHAIN 1..57
FT /note="Mambalgin-2"
FT /evidence="ECO:0000269|PubMed:23034652"
FT /id="PRO_0000420416"
FT DISULFID 3..19
FT /evidence="ECO:0000269|PubMed:24323786,
FT ECO:0000312|PDB:2MFA"
FT DISULFID 12..37
FT /evidence="ECO:0000269|PubMed:24323786,
FT ECO:0000312|PDB:2MFA"
FT DISULFID 41..49
FT /evidence="ECO:0000269|PubMed:24323786,
FT ECO:0000312|PDB:2MFA"
FT DISULFID 50..55
FT /evidence="ECO:0000269|PubMed:24323786,
FT ECO:0000312|PDB:2MFA"
FT STRAND 5..8
FT /evidence="ECO:0007829|PDB:2MFA"
FT STRAND 18..22
FT /evidence="ECO:0007829|PDB:2MFA"
FT STRAND 34..40
FT /evidence="ECO:0007829|PDB:2MFA"
FT STRAND 45..50
FT /evidence="ECO:0007829|PDB:2MFA"
SQ SEQUENCE 57 AA; 6547 MW; 004881FC91EEC5BA CRC64;
LKCFQHGKVV TCHRDMKFCY HNTGMPFRNL KLILQGCSSS CSETENNKCC STDRCNK
