C5I_ORNMO
ID C5I_ORNMO Reviewed; 168 AA.
AC Q5YD59;
DT 03-AUG-2022, integrated into UniProtKB/Swiss-Prot.
DT 23-NOV-2004, sequence version 1.
DT 03-AUG-2022, entry version 66.
DE RecName: Full=Complement inhibitor {ECO:0000303|PubMed:15699138};
DE Short=CI {ECO:0000312|EMBL:AAT65682.1};
DE Short=OmCI {ECO:0000303|PubMed:15699138, ECO:0000303|PubMed:17445829};
DE Flags: Precursor;
OS Ornithodoros moubata (Soft tick) (Argasid tick).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Acari;
OC Parasitiformes; Ixodida; Ixodoidea; Argasidae; Ornithodoros.
OX NCBI_TaxID=6938;
RN [1] {ECO:0000312|EMBL:AAT65682.1}
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 19-38, FUNCTION, SUBUNIT,
RP SUBCELLULAR LOCATION, AND RECOMBINANT EXPRESSION.
RC TISSUE=Salivary gland;
RX PubMed=15699138; DOI=10.4049/jimmunol.174.4.2084;
RA Nunn M.A., Sharma A., Paesen G.C., Adamson S., Lissina O., Willis A.C.,
RA Nuttall P.A.;
RT "Complement inhibitor of C5 activation from the soft tick Ornithodoros
RT moubata.";
RL J. Immunol. 174:2084-2091(2005).
RN [2] {ECO:0007744|PDB:2CM4, ECO:0007744|PDB:2CM9}
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 19-168 IN COMPLEX WITH RICINOLEIC
RP ACID, BINDING TO FATTY ACIDS, DISULFIDE BONDS, AND RECOMBINANT EXPRESSION.
RX PubMed=17445829; DOI=10.1016/j.jmb.2007.03.064;
RA Roversi P., Lissina O., Johnson S., Ahmat N., Paesen G.C., Ploss K.,
RA Boland W., Nunn M.A., Lea S.M.;
RT "The structure of OMCI, a novel lipocalin inhibitor of the complement
RT system.";
RL J. Mol. Biol. 369:784-793(2007).
RN [3] {ECO:0007744|PDB:3ZUI, ECO:0007744|PDB:3ZUO}
RP X-RAY CRYSTALLOGRAPHY (1.71 ANGSTROMS) OF 19-168 IN COMPLEX WITH
RP PALMITOLEIC ACID AND LEUKOTRIENE B4, DISULFIDE BONDS, RECOMBINANT
RP EXPRESSION, AND BIOASSAY.
RX PubMed=23625922; DOI=10.1074/jbc.m112.420331;
RA Roversi P., Ryffel B., Togbe D., Maillet I., Teixeira M., Ahmat N.,
RA Paesen G.C., Lissina O., Boland W., Ploss K., Caesar J.J.,
RA Leonhartsberger S., Lea S.M., Nunn M.A.;
RT "Bifunctional lipocalin ameliorates murine immune complex-induced acute
RT lung injury.";
RL J. Biol. Chem. 288:18789-18802(2013).
RN [4] {ECO:0007744|PDB:5HCC, ECO:0007744|PDB:5HCD, ECO:0007744|PDB:5HCE}
RP X-RAY CRYSTALLOGRAPHY (2.59 ANGSTROMS) OF 19-168 IN COMPLEX WITH HUMAN
RP COMPLEMENT C5 AND OTHER TICK COMPLEMENT INHBIBITORS RACI, AND DISULFIDE
RP BONDS.
RC TISSUE=Salivary gland;
RX PubMed=27018802; DOI=10.1038/nsmb.3196;
RA Jore M.M., Johnson S., Sheppard D., Barber N.M., Li Y.I., Nunn M.A.,
RA Elmlund H., Lea S.M.;
RT "Structural basis for therapeutic inhibition of complement C5.";
RL Nat. Struct. Mol. Biol. 23:378-386(2016).
RN [5] {ECO:0007744|PDB:6RQJ}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.50 ANGSTROMS) OF 22-168 IN COMPLEX WITH
RP HUMAN COMPLEMENT C5 AND THE TICK COMPLEMENT INHBIBITORS RACI1 AND CIRPT1,
RP AND DISULFIDE BONDS.
RX PubMed=31871188; DOI=10.1073/pnas.1909973116;
RA Reichhardt M.P., Johnson S., Tang T., Morgan T., Tebeka N., Popitsch N.,
RA Deme J.C., Jore M.M., Lea S.M.;
RT "An inhibitor of complement C5 provides structural insights into
RT activation.";
RL Proc. Natl. Acad. Sci. U.S.A. 117:362-370(2020).
RN [6]
RP PHARMACEUTICAL.
RX PubMed=34116700; DOI=10.1186/s13023-021-01890-6;
RA Sanchez-Tabernero S., Fajardo-Sanchez J., Weston-Davies W., Parekh M.,
RA Kriman J., Kaye S., Ahmad S.;
RT "Dual inhibition of complement component 5 and leukotriene B4 by topical
RT rVA576 in atopic keratoconjunctivis: TRACKER phase 1 clinical trial
RT results.";
RL Orphanet J. Rare Dis. 16:270-270(2021).
CC -!- FUNCTION: Bifunctional protein derived from blood-feeding ticks that
CC specifically prevents complement-mediated C5 activation and acts as a
CC scavenger for inflammatory modulators such as leukotriene B4 (LTB4). C5
CC and LTB4 binding activities are independent (PubMed:23625922). Inhibits
CC classical and alternative pathways of complement activation by
CC preventing the cleavage of complement C5 by both classical and
CC alternative C5 convertases (PubMed:15699138) (Probable). Inhibits
CC complement in all species tested (rabbit, rat, guinea pig, mouse, pig,
CC and human) (PubMed:27018802). Also binds fatty acids such as
CC palmitoleic acid and ricinoleic acid, as well as inflammatory
CC modulators LTB4 (and presumably arachidonic acid (AA)) that may be
CC sequestered to interfere with the host inflammatory response
CC (PubMed:23625922). Does not bind to leukotriene C4 and thromboxane B2
CC (PubMed:23625922). In vivo, when tested on the mouse model of immune
CC complex-induced acute lung injury (IC-ALI), shows a potent inhibitory
CC activity of the pathology, equally dependent on both C5 inhibition and
CC LTB4 binding for full activity (PubMed:23625922).
CC {ECO:0000269|PubMed:15699138, ECO:0000269|PubMed:23625922,
CC ECO:0000269|PubMed:27018802, ECO:0000305|PubMed:17445829}.
CC -!- SUBUNIT: Interacts with complement C5. {ECO:0000269|PubMed:15699138}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15699138}.
CC -!- TISSUE SPECIFICITY: Expressed in salivary glands.
CC {ECO:0000305|PubMed:15699138}.
CC -!- PHARMACEUTICAL: Is currently under several clinical trials by Akari
CC therapeutics under the name Nomacopan (previously Coversin). Is in
CC phase I to treat recalcitrant atopic keratoconjunctivitis (AKC)
CC (PubMed:34116700). Is in phase III to treat bullous pemphigoid (BP). Is
CC in phase III to treat severe pediatric hematopoietic stem cell
CC transplant-related thrombotic microangiopathy (HSCT-TMA). In addition,
CC is also under preclinical trials to treat complement-driven
CC inflammatory diseases, such as atypical hemolytic uremic syndrome
CC (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular
CC degeneration (AMD) and uveitis, thrombotic microangiopathy (TMA), and
CC paroxysmal nocturnal hemoglobinuria (PNH).
CC {ECO:0000269|PubMed:34116700}.
CC -!- SIMILARITY: Belongs to the calycin family. Lipocalin subfamily.
CC {ECO:0000305|PubMed:17445829}.
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DR EMBL; AY560803; AAT65682.1; -; mRNA.
DR PDB; 2CM4; X-ray; 1.90 A; A=19-168.
DR PDB; 2CM9; X-ray; 2.30 A; A=19-168.
DR PDB; 3ZUI; X-ray; 1.71 A; A=19-168.
DR PDB; 3ZUO; X-ray; 1.86 A; A/B/C/D=19-168.
DR PDB; 5HCC; X-ray; 2.59 A; C=21-168.
DR PDB; 5HCD; X-ray; 2.98 A; C=21-168.
DR PDB; 5HCE; X-ray; 3.12 A; C=21-168.
DR PDB; 6RQJ; EM; 3.50 A; C=22-168.
DR PDBsum; 2CM4; -.
DR PDBsum; 2CM9; -.
DR PDBsum; 3ZUI; -.
DR PDBsum; 3ZUO; -.
DR PDBsum; 5HCC; -.
DR PDBsum; 5HCD; -.
DR PDBsum; 5HCE; -.
DR PDBsum; 6RQJ; -.
DR SMR; Q5YD59; -.
DR EvolutionaryTrace; Q5YD59; -.
DR Gene3D; 2.40.128.20; -; 1.
DR InterPro; IPR012674; Calycin.
DR SUPFAM; SSF50814; SSF50814; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complement system impairing toxin; Direct protein sequencing;
KW Disulfide bond; Pharmaceutical; Secreted; Signal; Toxin.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..168
FT /note="Complement inhibitor"
FT /id="PRO_5004264249"
FT BINDING 54
FT /ligand="(12R)-hydroxy-(9Z)-octadecenoate"
FT /ligand_id="ChEBI:CHEBI:91295"
FT /evidence="ECO:0000269|PubMed:17445829,
FT ECO:0007744|PDB:2CM9"
FT BINDING 54
FT /ligand="(9Z)-hexadecenoate"
FT /ligand_id="ChEBI:CHEBI:32372"
FT /evidence="ECO:0000269|PubMed:23625922,
FT ECO:0007744|PDB:3ZUI"
FT BINDING 54
FT /ligand="leukotriene B4"
FT /ligand_id="ChEBI:CHEBI:57461"
FT /evidence="ECO:0000269|PubMed:23625922,
FT ECO:0007744|PDB:3ZUO"
FT BINDING 85
FT /ligand="(12R)-hydroxy-(9Z)-octadecenoate"
FT /ligand_id="ChEBI:CHEBI:91295"
FT /evidence="ECO:0000269|PubMed:17445829,
FT ECO:0007744|PDB:2CM4"
FT BINDING 85
FT /ligand="(9Z)-hexadecenoate"
FT /ligand_id="ChEBI:CHEBI:32372"
FT /evidence="ECO:0000269|PubMed:23625922,
FT ECO:0007744|PDB:3ZUI"
FT BINDING 87
FT /ligand="(9Z)-hexadecenoate"
FT /ligand_id="ChEBI:CHEBI:32372"
FT /evidence="ECO:0000269|PubMed:23625922,
FT ECO:0007744|PDB:3ZUI"
FT BINDING 87
FT /ligand="leukotriene B4"
FT /ligand_id="ChEBI:CHEBI:57461"
FT /evidence="ECO:0000269|PubMed:23625922,
FT ECO:0007744|PDB:3ZUO"
FT BINDING 107
FT /ligand="(12R)-hydroxy-(9Z)-octadecenoate"
FT /ligand_id="ChEBI:CHEBI:91295"
FT /evidence="ECO:0000269|PubMed:17445829,
FT ECO:0007744|PDB:2CM4"
FT BINDING 107
FT /ligand="leukotriene B4"
FT /ligand_id="ChEBI:CHEBI:57461"
FT /evidence="ECO:0000269|PubMed:23625922,
FT ECO:0007744|PDB:3ZUO"
FT BINDING 119
FT /ligand="(12R)-hydroxy-(9Z)-octadecenoate"
FT /ligand_id="ChEBI:CHEBI:91295"
FT /evidence="ECO:0000269|PubMed:17445829,
FT ECO:0007744|PDB:2CM4, ECO:0007744|PDB:2CM9"
FT BINDING 119
FT /ligand="leukotriene B4"
FT /ligand_id="ChEBI:CHEBI:57461"
FT /evidence="ECO:0000269|PubMed:23625922,
FT ECO:0007744|PDB:3ZUO"
FT BINDING 121
FT /ligand="(12R)-hydroxy-(9Z)-octadecenoate"
FT /ligand_id="ChEBI:CHEBI:91295"
FT /evidence="ECO:0000269|PubMed:17445829,
FT ECO:0007744|PDB:2CM4, ECO:0007744|PDB:2CM9"
FT BINDING 121
FT /ligand="leukotriene B4"
FT /ligand_id="ChEBI:CHEBI:57461"
FT /evidence="ECO:0000269|PubMed:23625922,
FT ECO:0007744|PDB:3ZUO"
FT DISULFID 24..146
FT /evidence="ECO:0000269|PubMed:17445829,
FT ECO:0000269|PubMed:23625922, ECO:0007744|PDB:2CM4,
FT ECO:0007744|PDB:2CM9, ECO:0007744|PDB:3ZUI,
FT ECO:0007744|PDB:3ZUO"
FT DISULFID 56..168
FT /evidence="ECO:0000269|PubMed:17445829,
FT ECO:0000269|PubMed:23625922, ECO:0007744|PDB:2CM4,
FT ECO:0007744|PDB:2CM9, ECO:0007744|PDB:3ZUI,
FT ECO:0007744|PDB:3ZUO"
FT DISULFID 118..147
FT /evidence="ECO:0000269|PubMed:17445829,
FT ECO:0000269|PubMed:23625922, ECO:0007744|PDB:2CM4,
FT ECO:0007744|PDB:2CM9, ECO:0007744|PDB:3ZUI,
FT ECO:0007744|PDB:3ZUO"
FT CONFLICT 25
FT /note="T -> S (in Ref. 1; AA sequence)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 168 AA; 18741 MW; C081BDA94A36C0E8 CRC64;
MLVLVTLIFS FSANIAYADS ESDCTGSEPV DAFQAFSEGK EAYVLVRSTD PKARDCLKGE
PAGEKQDNTL PVMMTFKNGT DWASTDWTFT LDGAKVTATL GNLTQNREVV YDSQSHHCHV
DKVEKEVPDY EMWMLDAGGL EVEVECCRQK LEELASGRNQ MYPHLKDC
