C3

Summary

C3 (complement C3, HGNC:1318) is a protein-coding gene on chromosome 19p13.3, encoding Complement C3 (P01024). Precursor of non-enzymatic components of the classical, alternative, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system.

Complement component C3 plays a central role in the activation of complement system. Its activation is required for both classical and alternative complement activation pathways. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form the mature protein, which is then further processed to generate numerous peptide products. The C3a peptide, also known as the C3a anaphylatoxin, modulates inflammation and possesses antimicrobial activity. Mutations in this gene are associated with atypical hemolytic uremic syndrome and age-related macular degeneration in human patients.

Source: NCBI Gene 718 — RefSeq curated summary.

At a glance

• Gene–disease (curated): atypical hemolytic-uremic syndrome with C3 anomaly (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 23
• Clinical variants (ClinVar): 1,876 total — 34 pathogenic, 40 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes
• MANE Select transcript: NM_000064

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1318
Approved symbol	C3
Name	complement C3
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	CPAMD1, ARMD9, C3a, C3b
Ensembl gene	ENSG00000125730
Ensembl biotype	protein_coding
OMIM	120700
Entrez	718

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 15 protein_coding, 14 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000245907, ENST00000594005, ENST00000594270, ENST00000594936, ENST00000595577, ENST00000596179, ENST00000596238, ENST00000596548, ENST00000597442, ENST00000598805, ENST00000599668, ENST00000599899, ENST00000600744, ENST00000600763, ENST00000601008, ENST00000601475, ENST00000602053, ENST00000602229, ENST00000695651, ENST00000695652, ENST00000695653, ENST00000695654, ENST00000695655, ENST00000695689, ENST00000695690, ENST00000695691, ENST00000695692, ENST00000695693, ENST00000879543, ENST00000879544, ENST00000879545, ENST00000879546, ENST00000952696

RefSeq mRNA: 1 — MANE Select: NM_000064 NM_000064

CCDS: CCDS32883

Canonical transcript exons

ENST00000245907 — 41 exons

Exon	Start	End
ENSE00000858128	6709684	6709842
ENSE00000858130	6710987	6711196
ENSE00000858137	6714352	6714446
ENSE00001053577	6714166	6714248
ENSE00001053582	6712257	6712406
ENSE00001053592	6718094	6718164
ENSE00001159750	6710639	6710845
ENSE00003052120	6720516	6720650
ENSE00003488647	6713189	6713315
ENSE00003553092	6719211	6719403
ENSE00003573711	6712508	6712623
ENSE00003607631	6713992	6714082
ENSE00003680550	6713407	6713509
ENSE00003787472	6718247	6718412
ENSE00003964598	6697652	6697794
ENSE00003964599	6707466	6707537
ENSE00003964600	6696593	6696659
ENSE00003964601	6681941	6682030
ENSE00003964602	6677704	6678023
ENSE00003964603	6679407	6679496
ENSE00003964604	6678152	6678287
ENSE00003964606	6690629	6690727
ENSE00003964607	6702127	6702212
ENSE00003964609	6686124	6686287
ENSE00003964610	6702471	6702579
ENSE00003964611	6692924	6693083
ENSE00003964612	6707076	6707273
ENSE00003964613	6682142	6682229
ENSE00003964614	6693412	6693487
ENSE00003964616	6680158	6680263
ENSE00003964618	6694431	6694634
ENSE00003964619	6696379	6696465
ENSE00003964621	6686746	6686902
ENSE00003964622	6684775	6684834
ENSE00003964623	6684388	6684439
ENSE00003964624	6679125	6679208
ENSE00003964626	6697344	6697556
ENSE00003964627	6707800	6707929
ENSE00003964628	6678372	6678455
ENSE00003964631	6684560	6684650
ENSE00003964632	6684988	6685146

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 169.7966 / max 27613.8564, expressed in 1268 samples.

FANTOM5 promoters (39 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178806	161.1458	1159
178738	1.2628	191
178774	0.8063	277
178772	0.5826	251
178805	0.4113	219
178748	0.4071	75
178737	0.4054	115
178730	0.2934	77
178741	0.2699	82
178773	0.2589	112

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
parietal pleura	UBERON:0002400	99.97	gold quality
right lobe of liver	UBERON:0001114	99.95	gold quality
palpebral conjunctiva	UBERON:0001812	99.95	gold quality
germinal epithelium of ovary	UBERON:0001304	99.92	gold quality
liver	UBERON:0002107	99.91	gold quality
pericardium	UBERON:0002407	99.85	gold quality
pleura	UBERON:0000977	99.80	gold quality
peritoneum	UBERON:0002358	99.78	gold quality
omental fat pad	UBERON:0010414	99.78	gold quality
mucosa of stomach	UBERON:0001199	99.75	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.74	gold quality
left uterine tube	UBERON:0001303	99.73	gold quality
right adrenal gland cortex	UBERON:0035827	99.72	gold quality
left adrenal gland cortex	UBERON:0035825	99.70	gold quality
left adrenal gland	UBERON:0001234	99.69	gold quality
right coronary artery	UBERON:0001625	99.69	gold quality
right adrenal gland	UBERON:0001233	99.68	gold quality
adrenal cortex	UBERON:0001235	99.65	gold quality
coronary artery	UBERON:0001621	99.57	gold quality
left coronary artery	UBERON:0001626	99.55	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.52	gold quality
lower esophagus	UBERON:0013473	99.50	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.50	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.48	gold quality
visceral pleura	UBERON:0002401	99.48	gold quality
upper lobe of left lung	UBERON:0008952	99.48	gold quality
adipose tissue	UBERON:0001013	99.44	gold quality
upper lobe of lung	UBERON:0008948	99.44	gold quality
colonic epithelium	UBERON:0000397	99.43	gold quality
gall bladder	UBERON:0002110	99.40	gold quality

Single-cell (SCXA)

Detected in 25 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	8623.79
E-MTAB-8530	yes	7171.50
E-MTAB-9543	yes	5069.43
E-HCAD-15	yes	4313.38
E-GEOD-81547	yes	2827.90
E-MTAB-10662	yes	2446.52
E-CURD-122	yes	2325.65
E-MTAB-10553	yes	1831.64
E-MTAB-9435	yes	1780.18
E-MTAB-6653	yes	1687.44
E-MTAB-8410	yes	1672.25
E-HCAD-11	yes	1361.98
E-MTAB-8495	yes	1225.80
E-GEOD-135922	yes	452.19
E-MTAB-6701	yes	126.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, CEBPD, CEBPG, CREB1, ESR1, ESR2, HNF4A, NCOA1, NFKB, NR1H2, NR1H3, NR1H4, PPARA, TFAP2A, TOX3

Literature-anchored findings (GeneRIF, showing 40)

• Allelic distribution of complement components BF, C4A, C4B, and C3 in Psoriasis vulgaris. (PMID:11803045)
• complement interaction with trypanosomatid promastigotes in normal human serum (PMID:11854358)
• genes of C3, hormone-sensitive lipase, and PPARgamma may exert a modifying effect on lipid and glucose metabolism in familial combined hyperlipidemia (PMID:11979403)
• The postprandial plasma C3 response is impaired in familial combined hyperlipidemia patients, probably as a result of a delayed response by C3 (the precursor for the biologically active acylation-stimulating protein) acting on free fatty acid metabolism. (PMID:12006395)
• results indicate that normal human hematopoietic stem and progenitor cells express functional C3aR and that the C3aR-C3a axis sensitizes the responses of these cells to SDF-1 (PMID:12511407)
• changes in acylation-stimulating protein and adiponectin are predictive of decreased apolipoprotein B and improved insulin action after gastric bypass surgery (PMID:12679444)
• The physiological interaction between glycyrrhizin (GL) and serum C3, and the inhibitory effects of GL, & glycyrrhetinic acid on the phosphorylation of C3 by casein kinase 2 (PMID:12761187)
• C3bi binds to integrin alpha M beta 2 (PMID:12816955)
• C4b and C3b do not undergo the same conformational changes upon binding to the C4BP mutants as during the interaction with the wild type C4BP, which then results in an observed loss of the cofactor activity (PMID:12893820)
• The analysis involved the data on nine polymorphic codominant loci: HP, GC, TF, PI, PGM1, GLO1, C3, ACP1, and ESD. The loci were selected by significance of differences in genotype frequencies between tuberculosis patients and healthy controls (PMID:12942785)
• IL-1alpha, IFN-gamma, and the combination of IL-1beta with IL-6 or IFN-gamma specifically enhanced C3 secretion by HepG2 cells (PMID:12967641)
• upon physiological inactivation, C3b2-IgG complexes retain dimeric inactivated C3b and C3dg, which allows bivalent binding to the corresponding complement receptors (PMID:14527961)
• ASP significantly predicted postprandial plasma triglyceride and NEFA clearance and, based on lower ASP, women may be more ASP sensitive than men (PMID:14563826)
• A premature termination codon in the C3 gene results in a lack of the protein in serum, correlating with acceleration of C3 mRNA decay in fibroblasts consistent with a nonsense-codon-mediated decay process. (PMID:14639503)
• Expressed in a bacterial system, a recombinant C3 segment of C345C module has substantial beta-sheet structure and internal disulfide bonds but does not inhibit complement hemolytic activity, and does not bind C6 or C7. (PMID:14662858)
• findings show a significant genetic contribution to variation in circulating levels of acylation-stimulating protein and an interesting pattern of genetic correlation (i.e., pleiotropy) with other risk factors associated with the metabolic syndrome (PMID:15090635)
• electrostatic calculations provide global and site-specific explanations of the physical causes that underlie the ionic strength dependence of C3d-CR2 association (PMID:15187133)
• HGF and IL-1ra adhesion-dependent release from human blood granulocytes and monocytes involves plasma IgG, complement C3 and beta2 integrin (PMID:15241561)
• MT1-MMP cleaves complement C3b (PMID:15381670)
• Transgenic mice expressing C3a/glial fibrillary acidic protein (GFAP) in the brain progress to severe experimental autoimmune encephalomyelitis during the chronic phase of the disease, with significant mortality compared with nontransgenic littermates. (PMID:15383607)
• thermodynamic analysis of interaction of C3 with its inhibitor, compstatin (PMID:15489226)
• A peptide (C3a) derived from the complement C3 protein has antimicrobial activity against E. coli, P. aeruginosa, E. faecalis, and C. albicans. (PMID:15550543)
• complement C3 expression is regulated by the bile acid receptor FXR (PMID:15590640)
• characterized the interaction between the first two short consensus repeats (SCR1-2) of complement receptor type 2 (CR2, CD21) and C3d (PMID:15713467)
• the open V-shaped structures formed by CR2 SCR 1-2, both when free and when bound to C3d, are optimal for the formation of a tight two-domain interaction with its ligand C3d (PMID:15713468)
• mapped the regions of C3 involved in conformational transition when hydrolyzed to C3(H2O) (PMID:15749882)
• iC3b interferes with monocyte-derived dendritic cell differentiation and IL-12 and IL-10 production is mediated via an ERK MAPK-dependent mechanism (PMID:15810889)
• determination of C5L2 as its receptor and the receptor’s role in mediating acylation stimulating protein triglyceride stimulation (PMID:15833747)
• C3 secretion induced by CD40L may represent a mechanism of amplification of tubulointerstitial damage associated with lymphocyte infiltration. (PMID:15872081)
• Moraxella catarrhalis UspA1/A2 exert their actions by absorbing and neutralizing C3 from serum and restrain complement activation (PMID:16148107)
• C3a increased the binding affinity of CXCL12 to human CXCR4(+)/C3aR(-), REH pro-B cells, which is compatible with a direct interaction between C3a and CXCL12 (PMID:16148115)
• crystal structures of native C3 and its final major proteolytic fragment C3c (PMID:16177781)
• properdin has a role in the assembly of the alternative pathway C3 convertases of complement (PMID:16301317)
• streptavidin-C3dg enhancement of BCR-induced [Ca2+]i responses required CD21 and CD19 expression and resulted in significantly enhanced CD19 and Lyn phosphorylation, with enhanced Lyn/CD19 associations (PMID:16339538)
• C3 gene is a priority candidate controlling risk for asthma and allergic disease in the Barbados population of African descent. (PMID:16355111)
• data cast new light on the mechanism of complement-mediated tissue injury in nonimmunological disorders (PMID:16449793)
• The differential expression of the complement proteins provides potentially useful biomarkers as well as evidence for the involvement of inflammatory processes in the pathogenesis of ALS and PD. (PMID:16516157)
• Complement C3a is continuously elevated in deep second-degree burned wounds in patients older than 60 years. (complement 3a) (PMID:16627066)
• Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2 (PMID:16670774)
• South Asians have elevated C3 & CRP levels; results suggest they have a greater level of chronic subclinical inflammation independent of family history of stroke; C3 is more likely to cluster with features of insulin resistance syndrome compared with CRP (PMID:16809564)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	c3b.2	ENSDARG00000001818
danio_rerio	c3a.1	ENSDARG00000012694
danio_rerio	c3a.6	ENSDARG00000043719
danio_rerio	c3a.3	ENSDARG00000052207
danio_rerio	c3a.5	ENSDARG00000053462
danio_rerio	c3a.2	ENSDARG00000087359
danio_rerio	c3b.1	ENSDARG00000093068
danio_rerio	c3a.4	ENSDARG00000093198
mus_musculus	C3	ENSMUSG00000024164
rattus_norvegicus	C3	ENSRNOG00000046834
drosophila_melanogaster	Tep4	FBGN0041180
drosophila_melanogaster	Tep3	FBGN0041181
drosophila_melanogaster	Tep2	FBGN0041182
drosophila_melanogaster	Tep1	FBGN0041183
caenorhabditis_elegans	tep-1	WBGENE00013969

Paralogs (8): C5 (ENSG00000106804), PZP (ENSG00000126838), CD109 (ENSG00000156535), CPAMD8 (ENSG00000160111), A2ML1 (ENSG00000166535), A2M (ENSG00000175899), C4B (ENSG00000224389), C4A (ENSG00000244731)

Protein

Protein identifiers

Complement C3 — P01024 (reviewed: P01024)

Alternative names: C3 and PZP-like alpha-2-macroglobulin domain-containing protein 1

All UniProt accessions (13): P01024, A0A8Q3SI05, A0A8Q3SI22, A0A8Q3SI34, A0A8Q3SI45, A0A8Q3WKN7, A0A8Q3WLS3, A0A8Q3WM02, M0QXZ3, M0QYC8, M0R0Q9, M0R1Q1, V9HWA9

UniProt curated annotations — full annotation on UniProt →

Function. Precursor of non-enzymatic components of the classical, alternative, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system. Non-enzymatic component of C5 convertase. Generated following cleavage by C3 convertase, it covalently attaches to the surface of pathogens, where it acts as an opsonin that marks the surface of antigens for removal. Complement C3b binds covalently via its reactive thioester, to cell surface carbohydrates or immune aggregates. Together with complement C4b, it then recruits the serine protease complement C2b to form the C5 convertase, which cleaves and activate C5, the next component of the complement pathways. In the alternative complement pathway, recruits the serine protease CFB to form the C5 convertase that cleaves and activates C5. Mediator of local inflammatory process released following cleavage by C3 convertase. Acts by binding to its receptor, C3AR1, activating G protein-coupled receptor signaling, promoting the phosphorylation, ARRB2-mediated internalization and endocytosis of C3AR1. C3a anaphylatoxin stimulates the activation of immune cells such as mast cells and basophilic leukocytes to release inflammation agents, such as cytokines, chemokines and histamine, which promote inflammation development. Also acts as potent chemoattractant for the migration of macrophages and neutrophils to the inflamed tissues, resulting in neutralization of the inflammatory triggers by multiple ways, such as phagocytosis and generation of reactive oxidants. Adipogenic hormone that stimulates triglyceride synthesis and glucose transport in adipocytes, regulating fat storage and playing a role in postprandial triglyceride clearance. Appears to stimulate triglyceride synthesis via activation of the PLC, MAPK and AKT signaling pathways. Acts by binding to its receptor, C5AR2, activating G protein-coupled receptor signaling, promoting the phosphorylation, ARRB2-mediated internalization and endocytosis of C5AR2. In contrast to C3a anaphylatoxin peptide, does not show pro-inflammatory activity. Acts as a chemoattractant for neutrophils in chronic inflammation.

Subunit / interactions. In absence of complement activation, the C3 precursor is first processed by the removal of 4 Arg residues, forming two chains, beta and alpha, linked by a disulfide bond. Complement C3b is composed of complement C3b and complement C3 beta chains that are associated via disulfide bonds. Non-enzymatic component of the C5 convertase, also named C4bC2bC3b, composed of the serine protease complement C2b (C2), complement C3b, as well as complement C4b (C4). Non-enzymatic component of the C5 convertase of the alternative complement pathways composed of the serine protease complement CFB and complement C3b. Interacts with CFP; interaction takes place together with CFB in the alternative complement system and allows the complex to become active. Interacts with CR1 (via Sushi 8 and Sushi 9 domains). Interacts with CFH. Interacts with CFH. Interacts with CR2. During pregnancy, C3dg exists as a complex (probably a 2:2:2 heterohexamer) with AGT and the proform of PRG2. Interacts with CR2 (via the N-terminal Sushi domains 1 and 2). (Microbial infection) C3b interacts with herpes simplex virus 1 (HHV-1) and herpes simplex virus 2 (HHV-2) envelope glycoprotein C; this interaction inhibits the activation of the complement system. (Microbial infection) Interacts with Staphylococcus aureus immunoglobulin-binding protein Sbi; this interaction prevents the association between C3dg and CR2. (Microbial infection) Interacts with Staphylococcus aureus protein Fib.

Subcellular location. Secreted Secreted. Cell surface Secreted.

Tissue specificity. Plasma. Produced in adipocytes and released into the plasma during both the fasting and postprandial periods.

Post-translational modifications. C3 precursor is first processed by the removal of 4 Arg residues, forming two chains, beta and alpha, linked by a disulfide bond. During activation of the complement systems, the alpha chain is cleaved into C3a and C3b by the C3 convertase: C3b stays linked to the beta chain, while C3a is released in the plasma. The alpha chain is cleaved by the serine protease complement C2b component of the C3 convertase to generate C3a and C3b following activation by the classical, lectin and GZMK complement systems. The alpha chain is cleaved by CFB component of the C3 convertase to generate C3a and C3b following activation by the alternative complement system. C3a is further processed by carboxypeptidases to release the C-terminal arginine residue generating the acylation stimulating protein (ASP). Levels of ASP are increased in adipocytes in the postprandial period and by insulin and dietary chylomicrons. Complement C3b is rapidly split in two positions by factor I (CFI) and a cofactor (CFH) to form iC3b (inactivated C3b) and C3f which is released. CFI and CFH catalyze proteolytic degradation of already-deposited complement C3b. Then iC3b is slowly cleaved (possibly by CFI) to form C3c (beta chain + alpha’ chain fragment 1 + alpha’ chain fragment 2), C3dg and C3f. Other proteases produce other fragments such as C3d or C3g. Upon activation, the internal thioester bond reacts with carbohydrate antigens on the target surface to form amide or ester bonds, leading to covalent association with the surface of pathogens. Complement C3b interacts with complement C4b via a thioester linkage. Phosphorylated by FAM20C in the extracellular medium. (Microbial infection) C3 is cleaved by Staphylococcus aureus aureolysin; this cleavage renders C3a and C3b inactive. C3b is rapidly degraded by host factors CFH and CFI preventing its deposition on the bacterial surface while C3a is further inactivated by aureolysin. (Microbial infection) Complement C3 beta chain is cleaved and inactivated by S.pyogenes SpeB. (Microbial infection) Cleaved by N.meningitidis NalP between Leu-744 and Gly-745, generating a slightly shorter C3 alpha form and a slightly longer C3 beta form. The C3b-like fragment is degraded in the presence of the complement regulators CFH and CFI, preventing its deposition on the bacterial surface.

Disease relevance. Complement component 3 deficiency (C3D) [MIM:613779] A rare defect of the complement classical pathway. Patients develop recurrent, severe, pyogenic infections because of ineffective opsonization of pathogens. Some patients may also develop autoimmune disorders, such as arthralgia and vasculitic rashes, lupus-like syndrome and membranoproliferative glomerulonephritis. The disease is caused by variants affecting the gene represented in this entry. Macular degeneration, age-related, 9 (ARMD9) [MIM:611378] A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Disease susceptibility is associated with variants affecting the gene represented in this entry. Hemolytic uremic syndrome, atypical, 5 (AHUS5) [MIM:612925] An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Disease susceptibility is associated with variants affecting the gene represented in this entry. Other genes may play a role in modifying the phenotype. Increased levels of C3 and its cleavage product ASP, are associated with obesity, diabetes and coronary heart disease. Short-term endurance training reduces baseline ASP levels and subsequently fat storage.

Activity regulation. Complement activation is inhibited by VSIG4.

Polymorphism. There are two alleles: C3S (C3 slow), the most common allele in all races and C3F (C3 fast), relatively frequent in Caucasians, less common in Black Americans, extremely rare in Orientals.

RefSeq proteins (1): NP_000055* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000020	Anaphylatoxin/fibulin	Domain
IPR001134	Netrin_domain	Domain
IPR001599	Macroglobln_a2	Domain
IPR001840	Anaphylatoxn_comp_syst_dom	Domain
IPR002890	MG2	Domain
IPR008930	Terpenoid_cyclase/PrenylTrfase	Homologous_superfamily
IPR008993	TIMP-like_OB-fold	Homologous_superfamily
IPR009048	A-macroglobulin_rcpt-bd	Domain
IPR011625	A2M_N_BRD	Domain
IPR011626	Alpha-macroglobulin_TED	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR018081	Anaphylatoxin_comp_syst	Homologous_superfamily
IPR018933	Netrin_module_non-TIMP	Domain
IPR019742	MacrogloblnA2_CS	Conserved_site
IPR035815	NTR_complement_C3	Domain
IPR036595	A-macroglobulin_rcpt-bd_sf	Homologous_superfamily
IPR040839	MG4	Domain
IPR041425	C3/4/5_MG1	Domain
IPR041555	MG3	Domain
IPR047565	Alpha-macroglob_thiol-ester_cl	Conserved_site
IPR048848	C3_CUB2	Domain
IPR049466	C3_CUB1	Domain
IPR050473	A2M/Complement_sys	Family

Pfam: PF00207, PF01759, PF01821, PF01835, PF07677, PF07678, PF07703, PF17789, PF17790, PF17791, PF21308, PF21406

Enzyme classification (BRENDA):

• EC 3.4.21.47 — alternative-complement-pathway C3/C5 convertase (BRENDA: 5 organisms, 28 substrates, 43 inhibitors, 19 Km, 19 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
COMPLEMENT COMPONENT C3	0.0059–0.0264	9
COMPLEMENT COMPONENT C5	—	8
T-BUTYLOXYCARBONYL-GLY-L-LEU-L-ALA-L-ARG-THIOBEN	2.75–5.63	2

UniProt features (274 total): strand 115, helix 44, turn 21, sequence variant 21, mutagenesis site 18, disulfide bond 14, chain 12, site 8, modified residue 8, glycosylation site 3, sequence conflict 3, domain 2, region of interest 2, signal peptide 1, peptide 1, cross-link 1

Structure

Experimental structures (PDB)

75 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2WY7	X-RAY DIFFRACTION	1.7
2WY8	X-RAY DIFFRACTION	1.7
7UE9	X-RAY DIFFRACTION	1.75
1C3D	X-RAY DIFFRACTION	1.8
6RMT	X-RAY DIFFRACTION	2
7BAG	X-RAY DIFFRACTION	2
1GHQ	X-RAY DIFFRACTION	2.04
3D5R	X-RAY DIFFRACTION	2.1
3OXU	X-RAY DIFFRACTION	2.1
4I6O	X-RAY DIFFRACTION	2.14
4ONT	X-RAY DIFFRACTION	2.15
2GOX	X-RAY DIFFRACTION	2.2
4ZH1	X-RAY DIFFRACTION	2.24
4HW5	X-RAY DIFFRACTION	2.25
3D5S	X-RAY DIFFRACTION	2.3
2XQW	X-RAY DIFFRACTION	2.31
9N1Z	X-RAY DIFFRACTION	2.31
6S0B	X-RAY DIFFRACTION	2.31
3RJ3	X-RAY DIFFRACTION	2.35
2A74	X-RAY DIFFRACTION	2.4
2QKI	X-RAY DIFFRACTION	2.4
5FO8	X-RAY DIFFRACTION	2.4
6RMU	X-RAY DIFFRACTION	2.4
4HWJ	X-RAY DIFFRACTION	2.6
5FOB	X-RAY DIFFRACTION	2.6
7PI6	X-RAY DIFFRACTION	2.6
6EHG	X-RAY DIFFRACTION	2.65
2NOJ	X-RAY DIFFRACTION	2.7
2WII	X-RAY DIFFRACTION	2.7
9U62	ELECTRON MICROSCOPY	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01024-F1	79.84	0.23

Antibody-complex structures (SAbDab): 11 — 3G6J, 6EHG, 6RU5, 6RUV, 6YO6, 7NOZ, 7QIV, 7UE9, 8HK2, 8I9L, 8OQ3

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (8): 541–542 ((microbial infection) cleavage; by s.pyogenes speb); 744–745 ((microbial infection) cleavage; by n.meningitidis nalp); 747–748 (cleavage; by carboxypeptidases); 748–749 (cleavage; by c3 convertase); 954–955 (cleavage; by factor i); 1303–1304 (cleavage; by factor i); 1320–1321 (cleavage; by factor i); 1663 (coordinates mg(2+) for interaction with complement factor b bb fragment (cfb))

Post-translational modifications (9): 38, 70, 297, 303, 672, 968, 1321, 1573, 1010–1013

Disulfide bonds (14): 559–816, 627–662, 693–720, 694–727, 707–728, 816, 873–1513, 1101–1158, 1358–1489, 1389–1458, 1506–1511, 1518–1590, 1537–1661, 1637–1646

Glycosylation sites (3): 85, 939, 1617

Mutagenesis-validated functional residues (18):

Position	Phenotype
404	decreased chemokine activity.
1029	minor effect on binding of c3d to cr2.
1030	impaired binding of c3d to cr2.
1032	impaired binding of c3d to cr2.
1035	no effect on binding of c3d to cr2.
1042	impaired binding of c3d to cr2.
1108–1109	impaired binding of c3d to cr2; when associated with a-1163.
1110	no effect on binding of c3d to cr2.
1115	no effect on binding of c3d to cr2.
1121	no effect on binding of c3d to cr2.
1140	no effect on binding of c3d to cr2.
1153	impaired binding of c3d to cr2.
1156	impaired binding of c3d to cr2.
1159	impaired binding of c3d to cr2.
1160	minor effect on binding of c3d to cr2.
1163	no effect on binding of c3d to cr2. impaired binding of c3d to cr2; when associated with 1108-r-r-1109.
1163	impaired binding of c3d to cr2.
1284	impaired binding of c3d to cr2.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-173736	Alternative complement activation
R-HSA-174577	Activation of C3 and C5
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-418594	G alpha (i) signalling events
R-HSA-6798695	Neutrophil degranulation
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-9660826	Purinergic signaling in leishmaniasis infection
R-HSA-977606	Regulation of Complement cascade

MSigDB gene sets: 622 (showing top): GOBP_REGULATION_OF_LIPID_STORAGE, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, MCLACHLAN_DENTAL_CARIES_UP, GOBP_REGULATION_OF_TRIGLYCERIDE_METABOLIC_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_B_CELL_ACTIVATION, GOCC_SECRETORY_GRANULE

GO Biological Process (34): positive regulation of type IIa hypersensitivity (GO:0001798), positive regulation of protein phosphorylation (GO:0001934), positive regulation of activation of membrane attack complex (GO:0001970), complement receptor mediated signaling pathway (GO:0002430), fatty acid metabolic process (GO:0006631), inflammatory response (GO:0006954), immune response (GO:0006955), complement activation (GO:0006956), complement activation, alternative pathway (GO:0006957), complement activation, classical pathway (GO:0006958), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), response to bacterium (GO:0009617), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of D-glucose transmembrane transport (GO:0010828), regulation of triglyceride biosynthetic process (GO:0010866), positive regulation of lipid storage (GO:0010884), neuron remodeling (GO:0016322), oviduct epithelium development (GO:0035846), B cell activation (GO:0042113), positive regulation of G protein-coupled receptor signaling pathway (GO:0045745), positive regulation of angiogenesis (GO:0045766), positive regulation of receptor-mediated endocytosis (GO:0048260), positive regulation of phagocytosis, engulfment (GO:0060100), amyloid-beta clearance (GO:0097242), complement-dependent cytotoxicity (GO:0097278), complement-mediated synapse pruning (GO:0150062), vertebrate eye-specific patterning (GO:0150064), complement activation, GZMK pathway (GO:0160257), positive regulation of apoptotic cell clearance (GO:2000427), immune system process (GO:0002376), lipid metabolic process (GO:0006629), innate immune response (GO:0045087), positive regulation of phagocytosis (GO:0050766)

GO Molecular Function (5): endopeptidase inhibitor activity (GO:0004866), signaling receptor binding (GO:0005102), C5L2 anaphylatoxin chemotactic receptor binding (GO:0031715), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (10): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), cell surface (GO:0009986), protein-containing complex (GO:0032991), secretory granule lumen (GO:0034774), azurophil granule lumen (GO:0035578), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Complement cascade	2
Initial triggering of complement	1
Adaptive Immune System	1
Class A/1 (Rhodopsin-like receptors)	1
Metabolism of proteins	1
GPCR downstream signalling	1
Innate Immune System	1
Post-translational protein modification	1
Cell recruitment (pro-inflammatory response)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
complement activation	2
signal transduction	2
type IIa hypersensitivity	1
regulation of type IIa hypersensitivity	1
positive regulation of type II hypersensitivity	1
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
activation of membrane attack complex	1
regulation of activation of membrane attack complex	1
positive regulation of complement activation	1
immune response-activating cell surface receptor signaling pathway	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
defense response	1
immune system process	1
response to stimulus	1
immune effector process	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
innate immune response	1
humoral immune response mediated by circulating immunoglobulin	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
response to other organism	1
positive regulation of cytokine production	1
vascular endothelial growth factor production	1
regulation of vascular endothelial growth factor production	1
regulation of D-glucose transmembrane transport	1
positive regulation of transmembrane transport	1
D-glucose transmembrane transport	1
triglyceride biosynthetic process	1
regulation of lipid biosynthetic process	1

Protein interactions and networks

STRING

2824 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C3	CFB	P00751	999
C3	CFH	P08603	999
C3	CD46	P15529	999
C3	CR1	P17927	999
C3	CFP	P27918	999
C3	VSIG4	Q9Y279	998
C3	C5AR2	Q9P296	996
C3	CD55	P08174	994
C3	SELP	P16109	991
C3	C4A	P01028	987
C3	C4A	P01028	986
C3	CFHR4	Q92496	985
C3	CR2	P20023	983
C3	C3AR1	Q16581	983
C3	ITGB2	P05107	980

IntAct

202 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
ASH2L	KMT2D	psi-mi:“MI:0914”(association)	0.890
MAPK6	HERC2	psi-mi:“MI:0914”(association)	0.840
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
C3	CFH	psi-mi:“MI:0407”(direct interaction)	0.740
C3	CR2	psi-mi:“MI:0407”(direct interaction)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
C3	CD46	psi-mi:“MI:0407”(direct interaction)	0.620
HCN1	C3	psi-mi:“MI:0915”(physical association)	0.620
C3	CFHR4	psi-mi:“MI:0407”(direct interaction)	0.610
CFHR4	C3	psi-mi:“MI:0915”(physical association)	0.610

BioGRID (173): C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), ITGB2 (Reconstituted Complex), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS), C3 (Affinity Capture-MS)

ESM2 similar proteins: A0AAQ4VMX2, A0RZC6, A8K7I4, C9XI63, C9XI66, I2C090, J3S836, P01023, P01024, P01025, P01026, P01027, P01029, P01030, P01031, P06684, P06756, P08649, P08650, P0C0L4, P0C0L5, P12247, P12387, P19069, P20740, P26007, P26008, P56652, P80746, P97280, P98093, Q01833, Q06033, Q0ZZJ6, Q2UVX4, Q3UU35, Q5RB37, Q61704, Q61739, Q63041

Diamond homologs: A0RZC6, I2C090, J3S836, P01024, P01025, P01026, P01027, P01032, P12247, P12387, P23667, P98093, P98094, Q00685, Q01833, Q0ZZJ6, Q2UVX4, Q6IE37, Q91132, P0C0L4, P0C0L5, Q6ZMU1, P01029, P01030, P08649, P19069, P12082, A0AAQ4VMX2, P20740, Q8IZJ3, P01023, P06238, P14046, P20742, P28666, Q03626, Q3UU35, Q5R4N8, Q61838, Q63041

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
CFH	“down-regulates activity”	C3	binding
CTSG	“up-regulates activity”	C3	cleavage
C3	“up-regulates activity”	C3AR1	binding
“C3 convertase complex (C3bBb)”	“up-regulates activity”	C3	cleavage
C3	“form complex”	“C5 convertase complex (C3bBbC3b)”	binding
C3	“up-regulates activity”	C3	cleavage
C3	“form complex”	“C3 convertase complex (C3bBb)”	binding
CFI	“down-regulates activity”	C3	cleavage
CSMD1	“down-regulates quantity”	C3	binding
CEBPB	“up-regulates quantity by expression”	C3	“transcriptional regulation”
C3	“form complex”	“C5 convertase complex”	binding
“C3 convertase complex”	“up-regulates activity”	C3	cleavage
CFHR1	“up-regulates activity”	C3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 170 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of Complement cascade	10	21.8×	1e-08
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	6	12.1×	1e-03
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	6	11.0×	2e-03
Epigenetic regulation by WDR5-containing histone modifying complexes	6	8.7×	5e-03
Transcriptional regulation by RUNX1	6	8.2×	6e-03
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	9	7.3×	7e-04
Post-translational protein phosphorylation	7	6.5×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
complement activation, alternative pathway	6	40.7×	2e-06
complement activation	7	29.9×	2e-06
complement activation, classical pathway	6	22.3×	9e-05
blood coagulation	7	8.3×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1876 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	34
Likely pathogenic	40
Uncertain significance	917
Likely benign	582
Benign	131

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1458199	NM_000064.4(C3):c.102del (p.Leu34fs)	Pathogenic
17058	NM_000064.4(C3):c.2354+1G>A	Pathogenic
17059	NC_000019.10:g.(6695981_6695999)_(6696810_6696831)del	Pathogenic
1711461	NM_000064.4(C3):c.1119+1G>A	Pathogenic
2108410	NM_000064.4(C3):c.2681dup (p.Leu894fs)	Pathogenic
2125661	NM_000064.4(C3):c.1602C>A (p.Tyr534Ter)	Pathogenic
2422288	NC_000019.9:g.(?6718085)(6720600_?)del	Pathogenic
2698807	NM_000064.4(C3):c.1196_1223dup (p.Lys408fs)	Pathogenic
2760684	NM_000064.4(C3):c.2209C>T (p.Gln737Ter)	Pathogenic
2828850	NM_000064.4(C3):c.2479C>T (p.Gln827Ter)	Pathogenic
2850008	NM_000064.4(C3):c.2965C>T (p.Gln989Ter)	Pathogenic
2853975	NM_000064.4(C3):c.1156C>T (p.Arg386Ter)	Pathogenic
2865025	NM_000064.4(C3):c.1777del (p.Val593fs)	Pathogenic
2880879	NM_000064.4(C3):c.1399_1406del (p.Pro467fs)	Pathogenic
3257541	NM_000064.4(C3):c.2558del (p.Asn853fs)	Pathogenic
3694852	NM_000064.4(C3):c.3958C>T (p.Arg1320Ter)	Pathogenic
4280162	NM_000064.4(C3):c.2002del (p.Arg668fs)	Pathogenic
4280170	NM_000064.4(C3):c.2696del (p.Val899fs)	Pathogenic
4280175	NM_000064.4(C3):c.3116dup (p.Glu1040fs)	Pathogenic
4280184	NM_000064.4(C3):c.3997del (p.Thr1333fs)	Pathogenic
4280242	NM_000064.4(C3):c.1432C>T (p.Arg478Ter)	Pathogenic
4280243	NM_000064.4(C3):c.1656G>A (p.Trp552Ter)	Pathogenic
4280244	NM_000064.4(C3):c.2542C>T (p.Arg848Ter)	Pathogenic
4280245	NM_000064.4(C3):c.3243C>G (p.Tyr1081Ter)	Pathogenic
4280246	NM_000064.4(C3):c.4258C>T (p.Gln1420Ter)	Pathogenic
4280249	NM_000064.4(C3):c.1004-2A>T	Pathogenic
4280250	NM_000064.4(C3):c.1119+1G>T	Pathogenic
4280252	NM_000064.4(C3):c.1480-1G>T	Pathogenic
4280287	NM_000064.4(C3):c.305dup (p.Asn103fs)	Pathogenic
4700265	NM_000064.4(C3):c.3808C>T (p.Gln1270Ter)	Pathogenic

SpliceAI

5040 predictions. Top by Δscore:

Variant	Effect	Δscore
19:6678019:TGAGG:T	acceptor_gain	1.0000
19:6678022:GG:G	acceptor_gain	1.0000
19:6678024:C:CC	acceptor_gain	1.0000
19:6678145:CACT:C	donor_loss	1.0000
19:6678146:ACTC:A	donor_loss	1.0000
19:6678148:TCA:T	donor_loss	1.0000
19:6678149:CACT:C	donor_loss	1.0000
19:6678150:A:AC	donor_gain	1.0000
19:6678150:A:T	donor_loss	1.0000
19:6678151:C:CT	donor_gain	1.0000
19:6678151:CT:C	donor_gain	1.0000
19:6678151:CTT:C	donor_gain	1.0000
19:6678151:CTTG:C	donor_gain	1.0000
19:6678151:CTTGG:C	donor_gain	1.0000
19:6678283:CGAGC:C	acceptor_gain	1.0000
19:6678284:GAGC:G	acceptor_gain	1.0000
19:6678285:AGC:A	acceptor_gain	1.0000
19:6678286:GC:G	acceptor_gain	1.0000
19:6678286:GCC:G	acceptor_loss	1.0000
19:6678287:CC:C	acceptor_gain	1.0000
19:6678288:C:CA	acceptor_loss	1.0000
19:6678288:C:CC	acceptor_gain	1.0000
19:6678293:G:C	acceptor_gain	1.0000
19:6678293:G:GC	acceptor_gain	1.0000
19:6678367:CTGA:C	donor_loss	1.0000
19:6678368:TGA:T	donor_loss	1.0000
19:6678369:GACCT:G	donor_loss	1.0000
19:6678371:CC:C	donor_loss	1.0000
19:6678371:CCTGA:C	donor_gain	1.0000
19:6678451:GTACA:G	acceptor_gain	1.0000

AlphaMissense

10921 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:6697522:C:G	C873S	0.999
19:6697523:A:T	C873S	0.999
19:6692961:A:C	F1118C	0.998
19:6692994:A:G	L1107P	0.998
19:6693081:A:G	L1078P	0.998
19:6693083:C:A	W1077C	0.998
19:6693083:C:G	W1077C	0.998
19:6693417:G:C	S1075R	0.998
19:6693417:G:T	S1075R	0.998
19:6693419:T:G	S1075R	0.998
19:6693435:G:C	F1069L	0.998
19:6693435:G:T	F1069L	0.998
19:6693437:A:G	F1069L	0.998
19:6694483:C:A	W1034C	0.998
19:6694483:C:G	W1034C	0.998
19:6697400:C:G	A914P	0.998
19:6710677:A:G	S550P	0.998
19:6713203:A:T	V330D	0.998
19:6678194:A:G	L1603P	0.997
19:6680184:A:T	V1477D	0.997
19:6685125:C:G	A1278P	0.997
19:6686274:C:A	W1220C	0.997
19:6686274:C:G	W1220C	0.997
19:6686276:A:G	W1220R	0.997
19:6686276:A:T	W1220R	0.997
19:6690666:A:G	L1151P	0.997
19:6692960:G:C	F1118L	0.997
19:6692960:G:T	F1118L	0.997
19:6692961:A:G	F1118S	0.997
19:6692962:A:G	F1118L	0.997

dbSNP variants (sampled 300 via entrez): RS1000213150 (19:6694242 G>A), RS1000311633 (19:6696054 A>C), RS1000384769 (19:6701936 T>C), RS1000400253 (19:6708188 G>C), RS1000680498 (19:6695910 T>C), RS1000875879 (19:6704300 A>G), RS1000946614 (19:6677340 G>A), RS1000976320 (19:6706253 T>C), RS1001074021 (19:6718759 T>A,C), RS1001117885 (19:6679545 A>C,G), RS1001422927 (19:6691351 C>T), RS1001461410 (19:6710168 G>A), RS1001537470 (19:6681520 T>C), RS1001663561 (19:6707027 TCCC>T,TCC), RS1001718925 (19:6688718 T>C,G)

Disease associations

OMIM: gene MIM:120700 | disease phenotypes: MIM:611378, MIM:612925, MIM:613779, MIM:614809, MIM:235400, MIM:610984

GenCC curated gene-disease

Disease	Classification	Inheritance
atypical hemolytic-uremic syndrome with C3 anomaly	Definitive	Autosomal dominant
complement component 3 deficiency	Definitive	Autosomal recessive
C3 glomerulonephritis	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
C3 glomerulonephritis	Moderate	AD
atypical hemolytic-uremic syndrome with C3 anomaly	Definitive	AD

Mondo (13): age related macular degeneration 9 (MONDO:0012659), atypical hemolytic-uremic syndrome with C3 anomaly (MONDO:0013043), complement component 3 deficiency (MONDO:0013417), C3 glomerulonephritis (MONDO:0013892), atypical hemolytic-uremic syndrome (MONDO:0016244), inherited retinal dystrophy (MONDO:0019118), kidney disorder (MONDO:0005240), focal segmental glomerulosclerosis (MONDO:0100313), hemolytic uremic syndrome, atypical, susceptibility to, 1 (MONDO:0009335), complement factor I deficiency (MONDO:0012594), familial hemolytic anemia (MONDO:0003689), primary ovarian failure (MONDO:0005387), membranoproliferative glomerulonephritis (MONDO:0002461)

Orphanet (8): Atypical hemolytic uremic syndrome (Orphanet:2134), Complement component 3 deficiency (Orphanet:280133), C3 glomerulonephritis (Orphanet:329931), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Shiga toxin-associated hemolytic uremic syndrome (Orphanet:90038), Immunodeficiency with factor I anomaly (Orphanet:200418), OBSOLETE: Atypical hemolytic uremic syndrome with C3 anomaly (Orphanet:93575), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

27 total (28 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000100	Nephrotic syndrome
HP:0000790	Hematuria
HP:0000793	Membranoproliferative glomerulonephritis
HP:0000822	Hypertension
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0001919	Acute kidney injury
HP:0001937	Microangiopathic hemolytic anemia
HP:0001954	Recurrent fever
HP:0002718	Recurrent bacterial infections
HP:0002725	Systemic lupus erythematosus
HP:0003138	Increased blood urea nitrogen
HP:0003259	Elevated circulating creatinine concentration
HP:0003581	Adult onset
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003774	Stage 5 chronic kidney disease
HP:0005421	Decreased circulating complement C3 concentration
HP:0005575	Hemolytic-uremic syndrome
HP:0006532	Recurrent pneumonia
HP:0011110	Recurrent tonsillitis
HP:0011463	Childhood onset
HP:0100519	Anuria
HP:0000556	Retinal dystrophy

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST000652_2	Age-related macular degeneration	1.000000e-10
GCST000653_8	Age-related macular degeneration	2.000000e-08
GCST000806_4	Age-related macular degeneration	1.000000e-08
GCST001100_10	Age-related macular degeneration	5.000000e-29
GCST001578_7	Age-related macular degeneration (geographic atrophy)	5.000000e-13
GCST001579_3	Age-related macular degeneration (choroidal neovascularisation)	1.000000e-12
GCST001679_10	Complement C3 and C4 levels	2.000000e-09
GCST001884_14	Age-related macular degeneration	1.000000e-41
GCST002219_1	Triglycerides	3.000000e-128
GCST003219_15	Advanced age-related macular degeneration	4.000000e-69
GCST003219_39	Advanced age-related macular degeneration	3.000000e-28
GCST003219_40	Advanced age-related macular degeneration	2.000000e-15
GCST004625_206	Monocyte count	5.000000e-16
GCST005359_3	Disease progression in age-related macular degeneration	1.000000e-09
GCST006585_1384	Blood protein levels	8.000000e-16
GCST006585_2782	Blood protein levels	1.000000e-08
GCST010723_6	Early age-related macular degeneration	2.000000e-10
GCST011834_4	Complement C3 levels	1.000000e-07
GCST90002388_33	Lymphocyte count	1.000000e-13
GCST90002393_638	Monocyte count	6.000000e-42
GCST90002394_436	Monocyte percentage of white cells	6.000000e-24
GCST90002407_354	White blood cell count	4.000000e-10
GCST90013407_166	Liver enzyme levels (gamma-glutamyl transferase)	1.000000e-14

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0004983	complement C3 measurement
EFO:0004530	triglyceride measurement
EFO:0005091	monocyte count
EFO:0008336	disease progression measurement
EFO:0004587	lymphocyte count
EFO:0007989	monocyte percentage of leukocytes
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D000745	Anemia, Hemolytic, Congenital	C15.378.050.141.150; C16.320.070
D065766	Atypical Hemolytic Uremic Syndrome	C12.050.351.968.419.936.463.500; C12.200.777.419.936.463.500; C12.950.419.936.463.500; C15.378.050.141.610.500; C15.378.140.855.925.500.500; C15.378.243.937.925.500.500
D015432	Glomerulonephritis, Membranoproliferative	C12.050.351.968.419.570.363.615; C12.200.777.419.570.363.615; C12.950.419.570.363.615; C20.425
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
D058499	Retinal Dystrophies	C11.768.585.658
C565169	Complement Component 3 Deficiency, Autosomal Recessive (supp.)
C572568	Complement Factor I Deficiency (supp.)
C566958	Macular Degeneration, Age-Related, 9 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4917 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2277984	Toxicity	3	clozapine	Metabolic Syndrome

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2230199	C3		0.00	0
rs2230205	C3		0.00	0
rs2250656	C3		0.00	0
rs2277984	C3	3	0.00	1	clozapine

Binding affinities (BindingDB)

6 measured of 6 human assays (6 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[(3S,5R)-3-ethoxy-8-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-8-azabicyclo[3.2.1]octan-1-yl]benzoic acid	IC50	1.3 nM	US-20250250267: NITROGEN-CONTAINING BRIDGED HETEROCYCLIC COMPOUND, PREPARATION METHOD THEREFOR, AND MEDICAL USE THEREOF
4-((1S,3S,5R)-8-((5-Cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-3-ethoxy-8-azabicycl o[3.2.1]octan-1-yl)benzoic acid 4	IC50	1.6 nM	US-20250250267: NITROGEN-CONTAINING BRIDGED HETEROCYCLIC COMPOUND, PREPARATION METHOD THEREFOR, AND MEDICAL USE THEREOF
4-[(3S,5R)-3-ethoxy-8-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-8-azabicyclo[3.2.1]octan-1-yl]benzoic acid	IC50	4.2 nM	US-20250250267: NITROGEN-CONTAINING BRIDGED HETEROCYCLIC COMPOUND, PREPARATION METHOD THEREFOR, AND MEDICAL USE THEREOF
4-((1S,3S,5R)-8-((5,7-Dimethyl-1H-indol-4-yl)methyl)-3-ethoxy-8-azabicyclo[3.2.1]oct an-1-yl)benzoic acid 3	IC50	4.9 nM	US-20250250267: NITROGEN-CONTAINING BRIDGED HETEROCYCLIC COMPOUND, PREPARATION METHOD THEREFOR, AND MEDICAL USE THEREOF
(2S,3S,4S,5R,6S)-6-((4-((1S,3S,5R)-3-Ethoxy-8-((5-methoxy-7-methyl-1H-indol-4-yl)m ethyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 5	IC50	30 nM	US-20250250267: NITROGEN-CONTAINING BRIDGED HETEROCYCLIC COMPOUND, PREPARATION METHOD THEREFOR, AND MEDICAL USE THEREOF
4-[(3R,5S)-3-ethoxy-8-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-8-azabicyclo[3.2.1]octan-1-yl]benzoic acid	IC50	72.2 nM	US-20250250267: NITROGEN-CONTAINING BRIDGED HETEROCYCLIC COMPOUND, PREPARATION METHOD THEREFOR, AND MEDICAL USE THEREOF

ChEMBL bioactivities

40 potent at pChembl≥5 of 51 total, top 38 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.80	Kd	1.6	nM	CHEMBL4241221
8.64	Kd	2.3	nM	CHEMBL4247287
7.82	Kd	15	nM	CHEMBL1791380
7.77	Kd	17	nM	CHEMBL427239
7.46	Kd	35	nM	CHEMBL219860
7.21	IC50	62	nM	CHEMBL4247287
6.96	Kd	110	nM	CHEMBL434556
6.92	Kd	120	nM	CHEMBL1791379
6.85	Kd	140	nM	CHEMBL252927
6.82	Kd	150	nM	CHEMBL1791382
6.69	IC50	205	nM	CHEMBL427239
6.69	IC50	205	nM	CHEMBL1791380
6.35	IC50	446	nM	CHEMBL219860
6.30	IC50	500	nM	CHEMBL427664
6.26	IC50	545	nM	CHEMBL434556
6.22	IC50	600	nM	CHEMBL430275
6.10	IC50	800	nM	CHEMBL408836
6.10	IC50	800	nM	CHEMBL439706
6.06	IC50	870	nM	CHEMBL1791379
5.96	IC50	1100	nM	CHEMBL2371730
5.92	IC50	1200	nM	CHEMBL252927
5.89	Kd	1300	nM	COMPSTATIN
5.85	IC50	1400	nM	CHEMBL437270
5.85	IC50	1400	nM	CHEMBL437245
5.82	IC50	1500	nM	CHEMBL2371729
5.82	IC50	1500	nM	CHEMBL445418
5.76	IC50	1740	nM	CHEMBL1791382
5.75	IC50	1800	nM	CHEMBL262797
5.57	IC50	2700	nM	CHEMBL269247
5.52	IC50	3000	nM	CHEMBL268084
5.40	IC50	4000	nM	CHEMBL3408038
5.22	IC50	6000	nM	CHEMBL414283
5.22	IC50	6000	nM	CHEMBL415619
5.22	IC50	6000	nM	CHEMBL265872
5.22	IC50	6000	nM	CHEMBL415601
5.16	IC50	7000	nM	CHEMBL429695
5.16	IC50	7000	nM	CHEMBL411957
5.02	IC50	9600	nM	CHEMBL268083

PubChem BioAssay actives

40 with measured affinity, of 152 total; 30 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4R,7S,10S,13S,19S,22S,25S,28S,31S,34R)-4-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]-methylcarbamoyl]-25-(3-amino-3-oxopropyl)-7-(3-carbamimidamidopropyl)-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13,17-dimethyl-28-[(1-methylindol-3-yl)methyl]-34-[[(2S,3S)-3-methyl-2-[[2-(methylamino)acetyl]amino]pentanoyl]amino]-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	1393241: Binding affinity to C3b derived from human plasma by SPR analysis	kd	0.0016	uM
2-[(4R,7S,10S,13S,19S,22S,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]-methylcarbamoyl]-25-(3-amino-3-oxopropyl)-7-(3-carbamimidamidopropyl)-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13,17-dimethyl-28-[(1-methylindol-3-yl)methyl]-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	1393240: Binding affinity to C3 derived from human plasma by ITC analysis	kd	0.0023	uM
(3S)-3-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-sulfanylpropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S,3S)-1-methoxy-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-(1-methylindol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-oxobutanoic acid	266544: Binding affinity to complement C3	kd	0.0150	uM
(3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(1-methylindol-3-yl)propanoyl]amino]-5-amino-5-oxopentanoyl]amino]-4-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-(5-fluoro-1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-oxobutanoic acid	266544: Binding affinity to complement C3	kd	0.0170	uM
(3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-amino-5-oxopentanoyl]amino]-4-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-(5-fluoro-1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-oxobutanoic acid	266544: Binding affinity to complement C3	kd	0.0350	uM
(3S)-3-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-sulfanylpropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S,3S)-1-methoxy-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-oxobutanoic acid	266544: Binding affinity to complement C3	kd	0.1100	uM
(3S)-3-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-sulfanylpropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S,3S)-1-methoxy-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-(5-methyl-1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-oxobutanoic acid	266544: Binding affinity to complement C3	kd	0.1200	uM
2-[(4R,7S,10S,13S,19S,22S,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-(3-carbamimidamidopropyl)-10-(1H-imidazol-5-ylmethyl)-19,28-bis(1H-indol-3-ylmethyl)-13-methyl-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	266544: Binding affinity to complement C3	kd	0.1400	uM
(3S)-4-[[(2S)-5-amino-1-[[(2S)-3-(5-fluoro-1H-indol-3-yl)-1-[[(2S)-1-[[(2R)-1-[[(2S,3S)-1-methoxy-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-sulfanylpropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-oxobutanoic acid	266544: Binding affinity to complement C3	kd	0.1500	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13-methyl-28-(naphthalen-2-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	0.5000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-28-[(4-benzoylphenyl)methyl]-7-[3-(diaminomethylideneamino)propyl]-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13-methyl-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	0.6000	uM
(2S,3R)-2-[[(4R,7S,10R,13S,19S,22R,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-25-(3-amino-3-oxopropyl)-28-(1-benzothiophen-3-yl)-22-(carboxymethyl)-7-[3-(diaminomethylideneamino)propyl]-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13,28-dimethyl-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacontane-4-carbonyl]amino]-3-hydroxybutanoic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	0.8000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-28-(1-benzothiophen-3-yl)-7-[3-(diaminomethylideneamino)propyl]-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13,28-dimethyl-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	0.8000	uM
(2S,3R)-2-[[(4R,7S,10R,13S,19S,22S,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-25-(3-amino-3-oxopropyl)-28-[(4-benzoylphenyl)methyl]-22-(carboxymethyl)-7-[3-(diaminomethylideneamino)propyl]-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13-methyl-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacontane-4-carbonyl]amino]-3-hydroxybutanoic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	1.1000	uM
2-[(4R,7S,10S,13S,19S,22S,25S,28S,31S,34R)-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-34-[[(2S,3S)-2-amino-3-methylpentanoyl]amino]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-10,13-bis(1H-imidazol-5-ylmethyl)-19-(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-28,31-di(propan-2-yl)-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	385501: Binding affinity to complement component C3 in human plasma by isothermal titration calorimetry	kd	1.3000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-28-(2,3-dihydro-1H-inden-1-yl)-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13-methyl-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	1.4000	uM
(2S,3R)-2-[[(4R,7S,10R,13S,19S,22R,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-25-(3-amino-3-oxopropyl)-22-(carboxymethyl)-7-[3-(diaminomethylideneamino)propyl]-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13-methyl-28-(naphthalen-2-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacontane-4-carbonyl]amino]-3-hydroxybutanoic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	1.4000	uM
(2S,3R)-2-[[(4R,7S,10R,13S,19S,22R,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-25-(3-amino-3-oxopropyl)-22-(carboxymethyl)-7-[3-(diaminomethylideneamino)propyl]-28-(2,3-dihydro-1H-inden-1-yl)-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13-methyl-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacontane-4-carbonyl]amino]-3-hydroxybutanoic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	1.5000	uM
(2S,3R)-2-[[(4S,7R,10S,13S,19S,22R,25S,28R,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-25-(3-amino-3-oxopropyl)-22-(carboxymethyl)-7-[3-(diaminomethylideneamino)propyl]-13-ethyl-10-(1H-imidazol-4-ylmethyl)-19,28-bis(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacontane-4-carbonyl]amino]-3-hydroxybutanoic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	1.5000	uM
(2S,3R)-2-[[(4R,7S,10R,13S,19S,22R,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-25-(3-amino-3-oxopropyl)-22-(carboxymethyl)-7-[3-(diaminomethylideneamino)propyl]-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13-methyl-28-(naphthalen-1-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacontane-4-carbonyl]amino]-3-hydroxybutanoic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	1.8000	uM
(2S,3S)-2-[[(4R,7S,10R,13S,19S,22R,25S,28R,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-25-(3-amino-3-oxopropyl)-22-(carboxymethyl)-7-[3-(diaminomethylideneamino)propyl]-10-(1H-imidazol-4-ylmethyl)-19,28-bis(1H-indol-3-ylmethyl)-13-methyl-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacontane-4-carbonyl]amino]-3-hydroxybutanoic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	2.7000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28R,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-28-[(4-hydroxyphenyl)methyl]-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13-methyl-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	3.0000	uM
2-[(4R,7S,10S,13S,19S,22S,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-(3-carbamimidamidopropyl)-10-(1H-imidazol-5-ylmethyl)-19-(1H-indol-3-ylmethyl)-28-[(1-methylindol-3-yl)methyl]-13-(naphthalen-1-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	1195921: Inhibition of C3 cleavage in human serum assessed as reduction in C3b formation compound preincubated for 15 mins measured 1 hr post LPS stimulation by ELISA	ic50	4.0000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28R,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-28-[(1R)-1-hydroxyethyl]-10,13-bis(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	6.0000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28R,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-28-(hydroxymethyl)-10,13-bis(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	6.0000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28R,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-28-benzyl-7-[3-(diaminomethylideneamino)propyl]-10,13-bis(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	6.0000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28R,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-10-(1H-imidazol-4-ylmethyl)-13,19,28-tris(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	6.0000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28R,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-10,13,28-tris(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	7.0000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28R,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-10,13-bis(1H-imidazol-4-ylmethyl)-19,28-bis(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	7.0000	uM
2-[(4R,7S,10R,13S,19S,22R,25S,28S,31S,34R)-34-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-4-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]carbamoyl]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-10-(1H-imidazol-4-ylmethyl)-19-(1H-indol-3-ylmethyl)-13-methyl-6,9,12,15,18,21,24,27,30,33-decaoxo-28-[(4-phosphonooxyphenyl)methyl]-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid	241156: Inhibitory concentration for human complement component C3 activation	ic50	9.6000	uM

CTD chemical–gene interactions

117 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, decreases reaction, affects cotreatment, increases expression	7
Tobacco Smoke Pollution	affects expression, decreases expression	4
Particulate Matter	decreases expression, increases abundance, increases expression, increases response to substance	4
Air Pollutants	decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation, increases mutagenesis	3
Cadmium	affects binding, affects expression, decreases expression, decreases reaction	3
Cyclosporine	decreases expression	3
aristolochic acid I	decreases expression, increases secretion	2
arsenite	decreases expression, decreases reaction, affects binding	2
sulforaphane	decreases expression, increases expression	2
sodium arsenite	affects methylation, decreases expression	2
entinostat	increases expression, affects cotreatment	2
Grape Seed Proanthocyanidins	affects cotreatment, increases expression, affects localization, decreases reaction	2
3’,4’-dimethoxy-alpha-naphthoflavone	decreases reaction, increases expression, decreases expression, increases activity, increases reaction	2
Cisplatin	affects cotreatment, affects expression, increases expression	2
Folic Acid	affects cotreatment, increases expression, affects expression, affects response to substance	2
Heparin	decreases expression	2
Methotrexate	affects cotreatment, increases expression	2
Nickel	affects binding, increases expression	2
Smoke	decreases expression, increases abundance	2
Valproic Acid	affects expression, decreases expression	2
4-hydroxy-7-oxo-5-heptenoic acid lactone	increases expression	1
Asian ginseng	decreases reaction, increases expression, affects cotreatment	1
lasiocarpine	decreases expression	1
bisphenol A	affects expression	1
chlortoluron	decreases expression	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	decreases expression	1
lead acetate	decreases expression	1
peroben	increases activity	1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3411192	Binding	Inhibition of C3 cleavage in human serum assessed as reduction in C3b formation compound preincubated for 15 mins measured 1 hr post LPS stimulation by ELISA	New compstatin peptides containing N-terminal extensions and non-natural amino acids exhibit potent complement inhibition and improved solubility characteristics. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7WD	Abcam Raji C3 KO	Cancer cell line	Male
CVCL_B9WW	Abcam THP-1 C3 KO	Cancer cell line	Male
CVCL_C6YX	Abcam PC-3 C3 KO	Cancer cell line	Male
CVCL_XM34	HAP1 C3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02574403	PHASE4	COMPLETED	Study Assessing an Algorithm-based Strategy of Eculizumab Discontinuation in Children and Adults With aHUS
NCT07308574	PHASE4	RECRUITING	Post-Marketing Clinical Study of Ravulizumab in Participants With Clinical aHUS
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	PHASE4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	PHASE4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	PHASE4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	PHASE4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	PHASE4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	PHASE4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	PHASE4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	PHASE4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	PHASE4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	PHASE4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	PHASE4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698	PHASE4	UNKNOWN	Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201	PHASE4	COMPLETED	Aliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141	PHASE4	COMPLETED	Idiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279	PHASE4	COMPLETED	Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333	PHASE4	COMPLETED	Comparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943	PHASE4	TERMINATED	Effect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479	PHASE4	COMPLETED	Increased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431	PHASE4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT01631149	PHASE4	COMPLETED	Effect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513	PHASE4	UNKNOWN	Efficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360	PHASE4	COMPLETED	ISCHEMIA-Chronic Kidney Disease Trial
NCT02311010	PHASE4	UNKNOWN	Practical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073	PHASE4	COMPLETED	Whole Body Vibration in Kidney Disease
NCT02444013	PHASE4	UNKNOWN	Folic Acid for Prevention of Contrast Induced Nephropathy
NCT02663713	PHASE4	COMPLETED	A Randomized, Pharmacodynamic Comparison of Low Dose Ticagrelor to Clopidogrel in Patients With Prior Myocardial Infarction
NCT02707809	PHASE4	COMPLETED	Effects of Dexmedetomidine on Microcirculation of Kidney Transplant Recipient