P0DKR6 · 3SX1_DENPO
- ProteinMambalgin-1
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
This three-finger toxin inhibits ASIC channels. It acts as a gating modifier toxin by decreasing the apparent proton sensitivity of activation and by slightly increasing the apparent proton sensitivity for inactivation (PubMed:23034652).
It binds more tightly to the closed state and to a much lesser extent the inactivated/desensitized state of ASIC1a isoform of ASIC1 (PubMed:23034652).
It interacts directly with the outside surface of the thumb domain of chicken ASIC1a (ASIC1a), but does not insert into the acidic pocket as suggested for mambalgin-2 (PubMed:29872539).
This binding leads to relocation of the thumb domain that could disrupt the acidic pocket of cASIC1a (PubMed:29872539).
It reversibly inhibits rat ASIC1a (IC50=3.4-55 nM), rat ASIC1a-ASIC2b (IC50=61 nM), rat ASIC1a-ASIC1b (IC50=72 nM), human ASIC1a (IC50=127-580 nM), chicken ASIC1a (IC50=123.6 nM), rat ASIC1b (IC50=22.2-203 nM), rat ASIC1a-ASIC2a (IC50=152-252 nM) (PubMed:23034652, PubMed:23624383, PubMed:24619065, PubMed:25873388, PubMed:26680001, PubMed:29872539).
In vivo, it shows a potent naloxone-resistant analgesic effect against acute and inflammatory pain upon central and peripheral injection (PubMed:23034652).
In addition, it also has an opioid-independent effect on both thermal and mechanical inflammatory pain after systemic administration and is effective against neuropathic pain (PubMed:26680001).
It binds more tightly to the closed state and to a much lesser extent the inactivated/desensitized state of ASIC1a isoform of ASIC1 (PubMed:23034652).
It interacts directly with the outside surface of the thumb domain of chicken ASIC1a (ASIC1a), but does not insert into the acidic pocket as suggested for mambalgin-2 (PubMed:29872539).
This binding leads to relocation of the thumb domain that could disrupt the acidic pocket of cASIC1a (PubMed:29872539).
It reversibly inhibits rat ASIC1a (IC50=3.4-55 nM), rat ASIC1a-ASIC2b (IC50=61 nM), rat ASIC1a-ASIC1b (IC50=72 nM), human ASIC1a (IC50=127-580 nM), chicken ASIC1a (IC50=123.6 nM), rat ASIC1b (IC50=22.2-203 nM), rat ASIC1a-ASIC2a (IC50=152-252 nM) (PubMed:23034652, PubMed:23624383, PubMed:24619065, PubMed:25873388, PubMed:26680001, PubMed:29872539).
In vivo, it shows a potent naloxone-resistant analgesic effect against acute and inflammatory pain upon central and peripheral injection (PubMed:23034652).
In addition, it also has an opioid-independent effect on both thermal and mechanical inflammatory pain after systemic administration and is effective against neuropathic pain (PubMed:26680001).
Miscellaneous
Negative results: has no effect on rat ASIC2a, rat ASIC3, rat ASIC1a-ASIC3 and rat ASIC1b-ASIC3 channels, as well as on TRPV1, P2RX2 (P2X2), HTR3A (5-HT3A), Nav1.8 (SCN10A), Cav3.2 (CACNA1H) and Kv1.2 (KCNA2) channels (PubMed:23034652).
Does not produce motor dysfunction, apathy, flaccid paralysis, convulsions or death upon central injections (intrathecal or intracerebroventricular) in mice (PubMed:23034652).
Does not produce motor dysfunction, apathy, flaccid paralysis, convulsions or death upon central injections (intrathecal or intracerebroventricular) in mice (PubMed:23034652).
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 48 | Important residue for inhibition of rat ASIC1a | ||||
Sequence: F | ||||||
Site | 49 | Important residue for inhibition of rat ASIC1a | ||||
Sequence: R | ||||||
Site | 53 | Key residue for inhibition of rat ASIC1a, probably binds to rat ASIC1a F-350 | ||||
Sequence: L | ||||||
Site | 54 | Important residue for inhibition of rat ASIC1a | ||||
Sequence: I | ||||||
Site | 55 | Important residue for inhibition of rat ASIC1a | ||||
Sequence: L |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | extracellular region | |
Molecular Function | ion channel regulator activity | |
Molecular Function | toxin activity |
Keywords
- Molecular function
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameMambalgin-1
- Short namesMamb-1
- Alternative names
Organism names
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Lepidosauria > Squamata > Bifurcata > Unidentata > Episquamata > Toxicofera > Serpentes > Colubroidea > Elapidae > Elapinae > Dendroaspis
Accessions
- Primary accessionP0DKR6
- Secondary accessions
Subcellular Location
Phenotypes & Variants
Pharmaceutical
Promising peptide that shows a potent analgesic effect against acute and inflammatory pain that can be as strong as morphine but resistant to naloxone, with much less tolerance and no respiratory distress.
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 26 | Small increase in inhibitory potency on cASIC1a. | ||||
Sequence: Q → A | ||||||
Mutagenesis | 27 | Important decrease in inhibitory potency on cASIC1a. | ||||
Sequence: H → A | ||||||
Mutagenesis | 29 | No change in inhibitory potency on cASIC1a. | ||||
Sequence: K → A | ||||||
Mutagenesis | 42 | 3.1-fold decrease in inhibitory potency of ASIC1a. | ||||
Sequence: H → A | ||||||
Mutagenesis | 44 | 3.9-fold decrease in inhibitory potency of ASIC1a. | ||||
Sequence: T → A | ||||||
Mutagenesis | 48 | Important (34-fold) decrease in inhibitory potency of ASIC1a. | ||||
Sequence: F → A | ||||||
Mutagenesis | 49 | Important (19-fold) decrease in inhibitory potency of ASIC1a. | ||||
Sequence: R → A | ||||||
Mutagenesis | 50 | 2.8-fold decrease in inhibitory potency of ASIC1a. | ||||
Sequence: N → A | ||||||
Mutagenesis | 51 | 5.1-fold decrease in inhibitory potency of ASIC1a. | ||||
Sequence: L → A | ||||||
Mutagenesis | 52 | 4.9-fold decrease in inhibitory potency of ASIC1a. | ||||
Sequence: K → A | ||||||
Mutagenesis | 53 | 2200-fold decrease in inhibitory potency of ASIC1a. | ||||
Sequence: L → A | ||||||
Mutagenesis | 54 | 16.3-fold decrease in inhibitory potency of ASIC1a. | ||||
Sequence: I → A | ||||||
Mutagenesis | 55 | 58-fold decrease in inhibitory potency of ASIC1a. | ||||
Sequence: L → A | ||||||
Mutagenesis | 78 | 1.5-fold decrease in inhibitory potency of ASIC1a. | ||||
Sequence: K → A |
PTM/Processing
Features
Showing features for signal, chain, disulfide bond.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Signal | 1-21 | |||||
Sequence: MKTLLLTLLVVTIVCLDLGYS | ||||||
Chain | PRO_0000420360 | 22-78 | Mambalgin-1 | |||
Sequence: LKCYQHGKVVTCHRDMKFCYHNTGMPFRNLKLILQGCSSSCSETENNKCCSTDRCNK | ||||||
Disulfide bond | 24↔40 | |||||
Sequence: CYQHGKVVTCHRDMKFC | ||||||
Disulfide bond | 33↔58 | |||||
Sequence: CHRDMKFCYHNTGMPFRNLKLILQGC | ||||||
Disulfide bond | 62↔70 | |||||
Sequence: CSETENNKC | ||||||
Disulfide bond | 71↔76 | |||||
Sequence: CSTDRC |
Keywords
- PTM
Expression
Tissue specificity
Expressed by the venom gland.
Structure
Family & Domains
Sequence similarities
Keywords
- Domain
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length78
- Mass (Da)8,853
- Last updated2012-11-28 v1
- ChecksumCC140CD5D3CB14FC
Mass Spectrometry
Keywords
- Technical term