ID   CYCTI_TITOB             Reviewed;          58 AA.
AC   A0A6P3CW73;
DT   23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT   23-FEB-2022, sequence version 2.
DT   03-AUG-2022, entry version 5.
DE   RecName: Full=Cyclotide trypsin inhibitor TopI1 {ECO:0000303|PubMed:32787139};
DE   Flags: Precursor;
OS   Tityus obscurus (Amazonian scorpion) (Tityus cambridgei).
OC   Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida;
OC   Scorpiones; Buthida; Buthoidea; Buthidae; Tityus.
OX   NCBI_TaxID=1221240;
RN   [1] {ECO:0000312|PDB:6MRQ}
RP   NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 32-52, SUBCELLULAR
RP   LOCATION, MASS SPECTROMETRY, FUNCTION, X-RAY CRYSTALLOGRAPHY (1.29
RP   ANGSTROMS) OF 24-55 IN COMPLEX WITH TRYPSIN, DISULFIDE BONDS, AMIDATION AT
RP   SER-56, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF LYS-44, CROSS-LINK,
RP   CYCLIZATION, AND SYNTHESIS OF 24-55.
RC   TISSUE=Telson;
RX   PubMed=32787139; DOI=10.1021/acs.jmedchem.0c00686;
RA   Mourao C.B.F., Brand G.D., Fernandes J.P.C., Prates M.V., Bloch C. Jr.,
RA   Barbosa J.A.R.G., Freitas S.M., Restano-Cassulini R., Possani L.D.,
RA   Schwartz E.F.;
RT   "Head-to-Tail Cyclization after Interaction with Trypsin: A Scorpion Venom
RT   Peptide that Resembles Plant Cyclotides.";
RL   J. Med. Chem. 63:9500-9511(2020).
CC   -!- FUNCTION: First cyclic scorpion trypsin inhibitor (Kd~0.5 nM). Does not
CC       inhibit chymotrypsin. {ECO:0000269|PubMed:32787139}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Temperature dependence:
CC         Is very stable at high temperature. {ECO:0000269|PubMed:32787139};
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:32787139}.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC       {ECO:0000305|PubMed:32787139}.
CC   -!- DOMAIN: Has the structural arrangement of an alpha-helix connected to
CC       antiparallel beta-sheets by disulfide bonds (CS-alpha/beta).
CC       {ECO:0000305|PubMed:32787139}.
CC   -!- PTM: This is a cyclic peptide. {ECO:0000269|PubMed:32787139}.
CC   -!- MASS SPECTROMETRY: Mass=3806.89; Method=MALDI;
CC       Evidence={ECO:0000269|PubMed:32787139};
CC   -!- MISCELLANEOUS: Trypsin inhibitor cleavage and cyclization are only
CC       observed in the presence of trypsin. It is suggested that the inhibitor
CC       Lys-55 is placed in the S1 pocket of trypsin, its C-terminal residue
CC       Ser-56 is cleaved, and the cyclization occurs via a peptide bond
CC       between residues Ile-24 and Lys-55. {ECO:0000305|PubMed:32787139}.
CC   -!- MISCELLANEOUS: Does not show activity on voltage-gated potassium
CC       channels (hKv1.1/KCNA1, hKv1.4/KCNA4, Kv10.1/KCNH1/EAG1,
CC       hKv11.1/KCNH2/ERG1, hKv11.2/KCNH6/ERG2, and hKv11.2/KCNH6/ERG2).
CC       {ECO:0000269|PubMed:32787139}.
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DR   EMBL; LR594010; -; NOT_ANNOTATED_CDS; mRNA.
DR   PDB; 6MRQ; X-ray; 1.29 A; I=24-55.
DR   PDBsum; 6MRQ; -.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
PE   1: Evidence at protein level;
KW   3D-structure; Amidation; Direct protein sequencing; Disulfide bond;
KW   Knottin; Protease inhibitor; Secreted; Serine protease inhibitor; Signal.
FT   SIGNAL          1..23
FT                   /evidence="ECO:0000255"
FT   CHAIN           24..56
FT                   /note="Cyclotide trypsin inhibitor TopI1"
FT                   /evidence="ECO:0000269|PubMed:32787139"
FT                   /id="PRO_0000454975"
FT   SITE            55..56
FT                   /note="Cleavage; by trypsin"
FT                   /evidence="ECO:0000305|PubMed:32787139"
FT   SITE            55
FT                   /note="Binds trypsin"
FT                   /evidence="ECO:0000269|PubMed:32787139"
FT   MOD_RES         56
FT                   /note="Serine amide"
FT                   /evidence="ECO:0000269|PubMed:32787139"
FT   DISULFID        28..45
FT                   /evidence="ECO:0000269|PubMed:32787139,
FT                   ECO:0007744|PDB:6MRQ"
FT   DISULFID        34..50
FT                   /evidence="ECO:0000269|PubMed:32787139,
FT                   ECO:0007744|PDB:6MRQ"
FT   DISULFID        38..52
FT                   /evidence="ECO:0000269|PubMed:32787139,
FT                   ECO:0007744|PDB:6MRQ"
FT   CROSSLNK        24..55
FT                   /note="Cyclopeptide (Ile-Lys)"
FT                   /evidence="ECO:0000269|PubMed:32787139"
FT   MUTAGEN         44
FT                   /note="K->A: No change in trypsin inhibition. At very high
FT                   concentrations (20 uM), small decrease in hKv1.1/KCNA1
FT                   inhibition."
FT                   /evidence="ECO:0000269|PubMed:32787139"
SQ   SEQUENCE   58 AA;  6482 MW;  79B7AC172E9D04BD CRC64;
     MKFIIVLLLL TALTLTSIPV IEGILKRCKT YDDCKDVCKA RKGKCEFGIC KCMIKSGK