CDKA_CONGR
ID CDKA_CONGR Reviewed; 95 AA.
AC A0A0A0VBX4;
DT 15-FEB-2017, integrated into UniProtKB/Swiss-Prot.
DT 10-FEB-2021, sequence version 2.
DT 03-AUG-2022, entry version 25.
DE RecName: Full=Alpha-conotoxin GeXXA {ECO:0000305};
DE AltName: Full=Alpha-D-conotoxin GeXXA {ECO:0000303|PubMed:26395518};
DE AltName: Full=Ge-5 {ECO:0000303|PubMed:30917600};
DE Flags: Precursor;
OS Conus generalis (General cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Strategoconus.
OX NCBI_TaxID=101304;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 46-66, SUBCELLULAR
RP LOCATION, DISULFIDE BOND, MUTAGENESIS OF 46-ASP--LEU-65 AND CYS-73, AND
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 46-95.
RC TISSUE=Venom, and Venom duct;
RX PubMed=26395518; DOI=10.1038/srep14261;
RA Xu S., Zhang T., Kompella S.N., Yan M., Lu A., Wang Y., Shao X., Chi C.,
RA Adams D.J., Ding J., Wang C.;
RT "Conotoxin alphaD-GeXXA utilizes a novel strategy to antagonize nicotinic
RT acetylcholine receptors.";
RL Sci. Rep. 5:14261-14268(2015).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-93.
RC TISSUE=Venom duct;
RX PubMed=30917600; DOI=10.3390/md17030193;
RA Yao G., Peng C., Zhu Y., Fan C., Jiang H., Chen J., Cao Y., Shi Q.;
RT "High-throughput identification and analysis of novel conotoxins from three
RT vermivorous cone snails by transcriptome sequencing.";
RL Mar. Drugs 17:0-0(2019).
CC -!- FUNCTION: Alpha-D-conopeptides act as non-competitive inhibitors of
CC nicotinic acetylcholine receptors (nAChR). This toxin has strong
CC inhibitory activity on rat alpha-9-alpha-10 (CHRNA9/CHRNA10)
CC (IC(50)=1.2 nM) and a moderate inhibitory activity on human alpha-7
CC (CHRNA7) (IC(50)=210 nM), rat alpha-3-beta-2 (CHRNA3/CHRNB2)
CC (IC(50)=498 nM), rat alpha-3-beta-4 (CHRNA3/CHRNB4) (IC(50)=614 nM) and
CC rat alpha-1-beta-1-delta-epsilon (CHRNA1/CHRNB1/CHRNE/CHRND)
CC (IC(50)=743 nM) subtypes. Shows a weaker inhibitory activity on human
CC alpha-9-alpha-10 (IC(50)=28 nM) than on the rat channel. This is
CC explained by a different residue in the probable binding site (His-31
CC in rat alpha-10 and Leu-31 in human). {ECO:0000269|PubMed:26395518}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:26395518}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:26395518}.
CC -!- DOMAIN: Displays a mini-granulin fold, a structure composed of two
CC short, stacked beta-hairpins connected by two parallel disulfide bonds.
CC This newly described fold is derived from the same cysteine
CC connectivity as knottins (ICK fold). The name 'mini-granulin fold'
CC comes from the structural homology with the N-terminal region of the
CC human granulin. {ECO:0000250|UniProtKB:W4VS16}.
CC -!- DOMAIN: The cysteine framework is XX (C-CC-C-CC-C-C-C-C).
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: Shows a very weak activity on alpha-4-beta-2 and alpha-
CC 4-beta-4 nAChR subtypes. {ECO:0000269|PubMed:26395518}.
CC -!- MISCELLANEOUS: The Val-47 is found by direct protein sequencing in the
CC protein described in Xu et al., 2015, and in the translated sequence in
CC Yao et al., 2019. The Ile-47 is only found in the translated sequence
CC described in Xu et al., 2015. {ECO:0000305|PubMed:26395518,
CC ECO:0000305|PubMed:30917600}.
CC -!- SIMILARITY: Belongs to the conotoxin D superfamily. {ECO:0000305}.
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DR EMBL; KM373785; AIW67484.1; -; mRNA.
DR PDB; 4X9Z; X-ray; 1.50 A; A/B=46-95.
DR PDBsum; 4X9Z; -.
DR AlphaFoldDB; A0A0A0VBX4; -.
DR SMR; A0A0A0VBX4; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0035792; C:host cell postsynaptic membrane; IEA:UniProtKB-KW.
DR GO; GO:0030550; F:acetylcholine receptor inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylcholine receptor inhibiting toxin;
KW Direct protein sequencing; Disulfide bond; Neurotoxin;
KW Postsynaptic neurotoxin; Secreted; Signal; Toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..45
FT /evidence="ECO:0000269|PubMed:26395518"
FT /id="PRO_0000438968"
FT CHAIN 46..95
FT /note="Alpha-conotoxin GeXXA"
FT /evidence="ECO:0000305|PubMed:26395518"
FT /id="PRO_5001970840"
FT DISULFID 51
FT /note="Interchain (with C-63)"
FT /evidence="ECO:0000269|PubMed:26395518,
FT ECO:0007744|PDB:4X9Z"
FT DISULFID 63
FT /note="Interchain (with C-51)"
FT /evidence="ECO:0000269|PubMed:26395518,
FT ECO:0007744|PDB:4X9Z"
FT DISULFID 64..73
FT /evidence="ECO:0000269|PubMed:26395518,
FT ECO:0007744|PDB:4X9Z"
FT DISULFID 69..81
FT /evidence="ECO:0000269|PubMed:26395518,
FT ECO:0007744|PDB:4X9Z"
FT DISULFID 74..91
FT /evidence="ECO:0000269|PubMed:26395518,
FT ECO:0007744|PDB:4X9Z"
FT DISULFID 79..93
FT /evidence="ECO:0000269|PubMed:26395518,
FT ECO:0007744|PDB:4X9Z"
FT MUTAGEN 46..65
FT /note="Missing: 70-fold decrease in inhibition of alpha-9-
FT alpha-10 nAChR and loss of inhibition of all other nAChR
FT subunits; when associated with S-73 (GeXXA-CTD, monomeric
FT form)."
FT MUTAGEN 73
FT /note="C->S: 70-fold decrease in inhibition of alpha-9-
FT alpha-10 nAChR and loss of inhibition of all other nAChR
FT subunits; when associated with 46-D--L-65 (GeXXA-CTD,
FT monomeric form)."
FT CONFLICT 4..8
FT /note="QEKMM -> LEMML (in Ref. 2)"
FT /evidence="ECO:0000305|PubMed:30917600"
FT CONFLICT 47
FT /note="V -> I (in Ref. 1; AIW67484)"
FT /evidence="ECO:0000305|PubMed:26395518"
FT STRAND 59..66
FT /evidence="ECO:0007829|PDB:4X9Z"
FT STRAND 80..84
FT /evidence="ECO:0007829|PDB:4X9Z"
FT TURN 85..87
FT /evidence="ECO:0007829|PDB:4X9Z"
FT STRAND 88..92
FT /evidence="ECO:0007829|PDB:4X9Z"
SQ SEQUENCE 95 AA; 10644 MW; A857722B03507FDD CRC64;
MPKQEKMMLV LLILPLPYCN AAGVTTVQWG GHGDGLDRYL QRGVRDVHRP CQSVRPGRVW
GKCCLTRLCS TMCCARADCT CVYHTWRGHG CSCVM
