MAMB1_DENAN
ID MAMB1_DENAN Reviewed; 57 AA.
AC A0A1Z0YU59;
DT 22-NOV-2017, integrated into UniProtKB/Swiss-Prot.
DT 22-NOV-2017, sequence version 2.
DT 25-MAY-2022, entry version 12.
DE RecName: Full=Mambaquaretin-1 {ECO:0000303|PubMed:28630289};
DE Short=MQ-1 {ECO:0000303|PubMed:28630289};
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, X-RAY CRYSTALLOGRAPHY
RP (1.06 ANGSTROMS) OF MUTANT NG/KA, MASS SPECTROMETRY, SYNTHESIS, AND
RP MUTAGENESIS OF SER-3; 1-ARG--PHE-4 AND 15-ASN-GLY-16.
RC TISSUE=Venom;
RX PubMed=28630289; DOI=10.1073/pnas.1620454114;
RA Ciolek J., Reinfrank H., Quinton L., Viengchareun S., Stura E.A., Vera L.,
RA Sigismeau S., Mouillac B., Orcel H., Peigneur S., Tytgat J., Droctove L.,
RA Beau F., Nevoux J., Lombes M., Mourier G., De Pauw E., Servent D.,
RA Mendre C., Witzgall R., Gilles N.;
RT "Green mamba peptide targets type-2 vasopressin receptor against polycystic
RT kidney disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:7154-7159(2017).
CC -!- FUNCTION: Interacts with vasopressin V2 receptor (V2R/AVPR2) and fully
CC inhibits three major signaling pathways of this receptor. Shows weak
CC inhibition on trypsin (PRSS1) (IC(50)=14.8 uM) and Kv1.1/KCNA1
CC (IC(50)=8.2 uM). In vivo, this protein shows an aquaretic effect. Urine
CC output increases and urine osmolality decreases dramatically under
CC treatment with this protein, without differences observed between
CC healthy and pcy mice (murine model of the autosomal-dominant polycystic
CC kidney disease (ADPKD)). This protein does not modify protein,
CC electrolyte and urea excretions in the urine samples, but produces a 3-
CC fold decrease of creatinine levels. Intraperitoneal injection of this
CC protein into the pcy mice significantly reduces the number of renal
CC cysts and the total area of cysts. {ECO:0000269|PubMed:28630289}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:28630289}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:28630289}.
CC -!- MASS SPECTROMETRY: Mass=6367.2; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:28630289};
CC -!- PHARMACEUTICAL: This protein represents a promising therapeutic agent
CC against polycystic kidney diseases (PKD). It shows renoprotective
CC effect on the murine model for PKD, since the number of renal cysts and
CC the total area of cysts is significantly reduced after treatment with
CC this protein. {ECO:0000269|PubMed:28630289}.
CC -!- MISCELLANEOUS: Does not interact with vasopression V1a, V1b and the
CC oxytocin receptors. Does not show activity on potassium (except Kv1.1),
CC sodium, and calcium (Cav1.2) channels. Does not show agonist and
CC antagonist activities on the 156 GPCR tested. Does not activate
CC pathways of the vasopression V2 receptor.
CC {ECO:0000269|PubMed:28630289}.
CC -!- SIMILARITY: Belongs to the venom Kunitz-type family. {ECO:0000305}.
CC -!- CAUTION: Personal communication with authors confirmed that residue 48
CC is an Isoleucine (as indicated in table S1 of PubMed:28630289) and not
CC a Leucine (as indicated in Fig.2a). {ECO:0000305|PubMed:28630289}.
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DR PDB; 5M4V; X-ray; 1.06 A; A=1-57.
DR PDBsum; 5M4V; -.
DR AlphaFoldDB; A0A1Z0YU59; -.
DR SMR; A0A1Z0YU59; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0015459; F:potassium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR CDD; cd00109; KU; 1.
DR Gene3D; 4.10.410.10; -; 1.
DR InterPro; IPR002223; Kunitz_BPTI.
DR InterPro; IPR036880; Kunitz_BPTI_sf.
DR InterPro; IPR020901; Prtase_inh_Kunz-CS.
DR Pfam; PF00014; Kunitz_BPTI; 1.
DR PRINTS; PR00759; BASICPTASE.
DR SMART; SM00131; KU; 1.
DR SUPFAM; SSF57362; SSF57362; 1.
DR PROSITE; PS00280; BPTI_KUNITZ_1; 1.
DR PROSITE; PS50279; BPTI_KUNITZ_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond;
KW G-protein coupled receptor impairing toxin; Ion channel impairing toxin;
KW Pharmaceutical; Potassium channel impairing toxin; Protease inhibitor;
KW Secreted; Serine protease inhibitor; Toxin;
KW Voltage-gated potassium channel impairing toxin.
FT CHAIN 1..57
FT /note="Mambaquaretin-1"
FT /evidence="ECO:0000269|PubMed:28630289"
FT /id="PRO_0000442231"
FT REGION 15..16
FT /note="Important for binding V2R"
FT /evidence="ECO:0000269|PubMed:28630289"
FT DISULFID 5..55
FT /evidence="ECO:0000305|PubMed:28630289"
FT DISULFID 14..38
FT /evidence="ECO:0000305|PubMed:28630289"
FT DISULFID 30..51
FT /evidence="ECO:0000305|PubMed:28630289"
FT MUTAGEN 1..4
FT /note="Missing: No change in affinity for V2R, loss of
FT activity on Kv1.1."
FT /evidence="ECO:0000269|PubMed:28630289"
FT MUTAGEN 3
FT /note="S->K: No change in affinity for V2R, 26-fold
FT increase in activity on Kv1.1."
FT /evidence="ECO:0000269|PubMed:28630289"
FT MUTAGEN 15..16
FT /note="NG->KA: 1000-fold decrease in affinity for V2R,
FT important increase in trypsin inhibition."
FT /evidence="ECO:0000269|PubMed:28630289"
FT HELIX 3..6
FT /evidence="ECO:0007829|PDB:5M4V"
FT STRAND 18..23
FT /evidence="ECO:0007829|PDB:5M4V"
FT TURN 25..27
FT /evidence="ECO:0007829|PDB:5M4V"
FT STRAND 28..35
FT /evidence="ECO:0007829|PDB:5M4V"
FT STRAND 37..39
FT /evidence="ECO:0007829|PDB:5M4V"
FT STRAND 45..47
FT /evidence="ECO:0007829|PDB:5M4V"
FT HELIX 48..55
FT /evidence="ECO:0007829|PDB:5M4V"
SQ SEQUENCE 57 AA; 6377 MW; CA79C78B3506D076 CRC64;
RPSFCNLPVK PGPCNGFFSA FYYSQKTNKC HSFTYGGCKG NANRFSTIEK CRRTCVG
