ID   CA1A_CONMD              Reviewed;          14 AA.
AC   P0DQQ6;
DT   29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT   29-SEP-2021, sequence version 1.
DT   23-FEB-2022, entry version 2.
DE   RecName: Full=Alpha-conotoxin MilIA {ECO:0000303|PubMed:31527432};
OS   Conus milneedwardsi (Glory of India cone snail).
OC   Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC   Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Leptoconus.
OX   NCBI_TaxID=2825866;
RN   [1]
RP   PROTEIN SEQUENCE, FUNCTION, AMIDATION AT CYS-14, SUBCELLULAR LOCATION, MASS
RP   SPECTROMETRY, AND MUTAGENESIS OF MET-9; ASN-10; 1-ASP-MET-2 AND
RP   9-MET--HIS-11.
RC   TISSUE=Venom;
RX   PubMed=31527432; DOI=10.3390/md17090535;
RA   Peigneur S., Devi P., Seldeslachts A., Ravichandran S., Quinton L.,
RA   Tytgat J.;
RT   "Structure-function elucidation of a new alpha-conotoxin, MilIA, from Conus
RT   milneedwardsi.";
RL   Mar. Drugs 17:0-0(2019).
CC   -!- FUNCTION: Alpha-conotoxins act on postsynaptic membranes, they bind to
CC       the nicotinic acetylcholine receptors (nAChR) and thus inhibit them.
CC       This toxin inhibits muscle nAChRs with moderate potency (IC(50)=11 uM
CC       on alpha-1-beta-1-delta-epsilon/CHRNA1-CHRNB1-CHRND-CHRNE (adult), and
CC       IC(50)=13 uM on alpha-1-beta-1-gamma-delta/CHRNA1-CHRNB1-CHRNG-CHRND
CC       (fetal)). {ECO:0000269|PubMed:31527432}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:31527432}.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC       {ECO:0000305|PubMed:31527432}.
CC   -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha3/5 pattern.
CC       {ECO:0000305}.
CC   -!- MASS SPECTROMETRY: Mass=1620.92; Method=MALDI;
CC       Evidence={ECO:0000269|PubMed:31527432};
CC   -!- MISCELLANEOUS: Is not active on all neuronal nAChR tested (alpha-2-
CC       beta-4/CHRNA2-CHRNB4, alpha-4-beta-2/CHRNA4-CHRNB2, alpha-4-beta-
CC       4/CHRNA4-CHRNB4, alpha-7/CHRNA7, and alpha-9-alpha-10/CHRNA9-CHRNA10)
CC       (IC(50)>10 uM). {ECO:0000269|PubMed:31527432}.
CC   -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}.
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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   Acetylcholine receptor inhibiting toxin; Amidation;
KW   Direct protein sequencing; Disulfide bond; Neurotoxin;
KW   Postsynaptic neurotoxin; Secreted; Toxin.
FT   PEPTIDE         1..14
FT                   /note="Alpha-conotoxin MilIA"
FT                   /evidence="ECO:0000269|PubMed:31527432"
FT                   /id="PRO_0000453220"
FT   MOD_RES         14
FT                   /note="Cysteine amide"
FT                   /evidence="ECO:0000269|PubMed:31527432"
FT   DISULFID        3..8
FT                   /evidence="ECO:0000250|UniProtKB:P01521"
FT   DISULFID        4..14
FT                   /evidence="ECO:0000250|UniProtKB:P01521"
FT   MUTAGEN         1..2
FT                   /note="DM->R: In MilIA[Delta-1, M2R, M9G, N10K, H11K];
FT                   important increase in ability to inhibit both fetal (820-
FT                   fold) and adult (450-fold) muscle nAChRs, as well as gain
FT                   of ability to inhibit alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR
FT                   (IC(50)=0.5 uM)."
FT                   /evidence="ECO:0000269|PubMed:31527432"
FT   MUTAGEN         9..11
FT                   /note="MNH->GKK: In MilIA[Delta-1, M2R, M9G, N10K, H11K];
FT                   important increase in ability to inhibit both fetal (820-
FT                   fold) and adult (450-fold) muscle nAChRs, as well as gain
FT                   of ability to inhibit alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR
FT                   (IC(50)=0.5 uM)."
FT                   /evidence="ECO:0000269|PubMed:31527432"
FT   MUTAGEN         9
FT                   /note="M->G: Important increase (22-fold) in ability to
FT                   inhibit fetal muscle nAChR, and loss of ability to inhibit
FT                   adult nAChR. This modification allows to strongly
FT                   discriminate between the two types of muscle nAChRs."
FT                   /evidence="ECO:0000269|PubMed:31527432"
FT   MUTAGEN         10
FT                   /note="N->K: Moderate increase (3-fold) in ability to
FT                   inhibit fetal muscle nAChR, and loss of ability to inhibit
FT                   adult nAChR. This modification allows to strongly
FT                   discriminate between the two types of muscle nAChRs."
FT                   /evidence="ECO:0000269|PubMed:31527432"
SQ   SEQUENCE   14 AA;  1626 MW;  DEFF731C342BCABD CRC64;
     DMCCHPACMN HFNC