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- PDB-9qk2: Structure of the Complement classical and lectin pathway C3 conve... -

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Basic information

Entry
Database: PDB / ID: 9qk2
TitleStructure of the Complement classical and lectin pathway C3 convertase in complex with substrate C3
Components
  • Anti-C4b nanobody B12
  • Complement C2
  • Complement C3
  • Complement C4-A
KeywordsIMMUNE SYSTEM / C3 convertase / Complement classical pathway / convertase-substrate complex / C3 substrate
Function / homology
Function and homology information


classical-complement-pathway C3/C5 convertase / C5L2 anaphylatoxin chemotactic receptor binding / oviduct epithelium development / regulation of triglyceride biosynthetic process / complement component C1q complex binding / positive regulation of activation of membrane attack complex / response to thyroid hormone / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / Alternative complement activation ...classical-complement-pathway C3/C5 convertase / C5L2 anaphylatoxin chemotactic receptor binding / oviduct epithelium development / regulation of triglyceride biosynthetic process / complement component C1q complex binding / positive regulation of activation of membrane attack complex / response to thyroid hormone / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / Alternative complement activation / complement-mediated synapse pruning / positive regulation of type IIa hypersensitivity / Activation of C3 and C5 / positive regulation of lipid storage / complement activation, GZMK pathway / positive regulation of phagocytosis, engulfment / positive regulation of G protein-coupled receptor signaling pathway / symbiont cell surface / complement-dependent cytotoxicity / positive regulation of D-glucose transmembrane transport / complement receptor mediated signaling pathway / complement activation, alternative pathway / complement activation / Initial triggering of complement / neuron remodeling / endopeptidase inhibitor activity / amyloid-beta clearance / B cell activation / complement activation, classical pathway / positive regulation of vascular endothelial growth factor production / Purinergic signaling in leishmaniasis infection / response to nutrient / Regulation of Complement cascade / Peptide ligand-binding receptors / response to bacterium / Post-translational protein phosphorylation / fatty acid metabolic process / positive regulation of protein phosphorylation / positive regulation of receptor-mediated endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / positive regulation of angiogenesis / azurophil granule lumen / secretory granule lumen / blood microparticle / response to lipopolysaccharide / G alpha (i) signalling events / immune response / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / inflammatory response / receptor ligand activity / signaling receptor binding / serine-type endopeptidase activity / axon / neuronal cell body / Neutrophil degranulation / synapse / dendrite / cell surface / signal transduction / protein-containing complex / proteolysis / : / extracellular exosome / extracellular region / metal ion binding / plasma membrane
Similarity search - Function
: / : / Complement C4, MG1 domain / Complement C4A/B CUB C-terminal domain / Complement B/C2 / Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment ...: / : / Complement C4, MG1 domain / Complement C4A/B CUB C-terminal domain / Complement B/C2 / Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Anaphylatoxin, complement system domain / : / Alpha-macro-globulin thiol-ester bond-forming region / Anaphylatoxin domain signature. / Anaphylatoxin, complement system / Anaphylatoxin/fibulin / Anaphylotoxin-like domain / Anaphylatoxin domain profile. / Anaphylatoxin homologous domain / Netrin C-terminal Domain / Netrin module, non-TIMP type / UNC-6/NTR/C345C module / Macroglobulin domain MG4 / Macroglobulin domain MG4 / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain / Macroglobulin domain MG3 / A-macroglobulin receptor / Netrin domain / NTR domain profile. / Alpha-2-macroglobulin / Macroglobulin domain / Tissue inhibitor of metalloproteinases-like, OB-fold / Alpha-2-macroglobulin, bait region domain / Alpha-macroglobulin-like, TED domain / Alpha-2-macroglobulin family / MG2 domain / A-macroglobulin TED domain / Alpha-2-macroglobulin bait region domain / Alpha-2-Macroglobulin / Alpha-2-macroglobulin family / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / von Willebrand factor type A domain / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / VWFA domain profile. / von Willebrand factor (vWF) type A domain / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Immunoglobulin-like fold / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Complement C3 / Complement C2 / Complement C4-A
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsDe la O Becerra, K.I. / Brondijk, T.H.C. / Gros, P.
Funding support Mexico, Netherlands, European Union, 3items
OrganizationGrant numberCountry
Consejo Nacional de Ciencia y Tecnologia (CONACYT)CVU 604718 Mexico
Netherlands Organisation for Scientific Research (NWO)01.80.104.00 Netherlands
European Research Council (ERC)787241European Union
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into C3 convertase activity of the classical pathway of complement.
Authors: Karla I De la O Becerra / T Harma C Brondijk / Itziar Serna Martin / Piet Gros /
Abstract: Immune protection by the complement system depends on C3 cleavage by C3 convertases that is critical to all three activation pathways. Structural data on convertase formation in the classical pathway ...Immune protection by the complement system depends on C3 cleavage by C3 convertases that is critical to all three activation pathways. Structural data on convertase formation in the classical pathway and on C3-substrate binding to convertases is lacking. We present the cryo-EM structures of the proconvertase (C4b2), convertase (C4b2b), and convertase-substrate complex (C4b2b-C3) of the classical pathway. The data show that C2 and C4b form proconvertases and convertases like factor B and C3b of the alternative pathway. Substrate C3 binds C4b of the convertase through two interfaces: one also found in the SCIN-inhibited C3bBb dimer, and another facilitated by conformational changes in C3. Bending of C3 and swinging of the C2 protease bring the C3-scissile loop into the active site. The second, charged, C4b-interaction site favors C3- substrate binding, but upon cleavage repels product C3b. Thus, a charge switch-over mechanism effects the catalytic turnover of the convertases producing opsonin C3b.
History
DepositionMar 19, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 24, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Complement C4-A
C: Complement C4-A
E: Complement C2
B: Complement C4-A
D: Anti-C4b nanobody B12
F: Complement C3
G: Complement C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,052,21816
Polymers1,050,4247
Non-polymers1,7949
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 3 types, 6 molecules ACBEFG

#1: Protein Complement C4-A / Acidic complement C4 / C3 and PZP-like alpha-2-macroglobulin domain-containing protein 2


Mass: 192993.203 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: blood plasma / References: UniProt: P0C0L4
#2: Protein Complement C2 / C3/C5 convertase


Mass: 83347.766 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Active site mutation S679A / Source: (gene. exp.) Homo sapiens (human) / Gene: C2 / Details (production host): CMV promotor / Cell line (production host): HEK293 E+ / Production host: Homo sapiens (human)
References: UniProt: P06681, classical-complement-pathway C3/C5 convertase
#4: Protein Complement C3 / C3 and PZP-like alpha-2-macroglobulin domain-containing protein 1


Mass: 187387.016 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: blood plasma / References: UniProt: P01024

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Antibody / Sugars / Non-polymers , 3 types, 10 molecules D

#3: Antibody Anti-C4b nanobody B12


Mass: 13322.883 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Plasmid: pET-X13 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-(DE3)pLysS
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Classical and lectin pathway C3 convertase in complex with substrate C3
Type: COMPLEX / Entity ID: #1-#4 / Source: NATURAL
Molecular weightValue: 0.452 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human) / Tissue: blood plasma
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMHEPES1
32 mMMagnesium chlorideMgCl21
42 mMClacium chlorideCaCl21
SpecimenConc.: 0.23 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: C4b and C3 were purified linked through 2 non-inhibitory nanobodies, for the classical and lectin pathways, targeting C4b-MG8 and C3-C345C domains. Then the complex was formed by addition of ...Details: C4b and C3 were purified linked through 2 non-inhibitory nanobodies, for the classical and lectin pathways, targeting C4b-MG8 and C3-C345C domains. Then the complex was formed by addition of C2 and preactivated C1s before freezing the grids.
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K

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Electron microscopy imaging

MicroscopyModel: TFS TALOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2600 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4276

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Processing

EM software
IDNameVersionCategory
1cryoSPARCv4.2.0/4particle selection
2EPU2.10.0image acquisition
4cryoSPARCv4.2.0/4CTF correction
7UCSF ChimeraX1.7model fitting
9cryoSPARCv4.2.0/4initial Euler assignment
10cryoSPARCv4.2.0/4final Euler assignment
11cryoSPARCv4.2.0/4classification
12cryoSPARCv4.2.0/43D reconstruction
19PHENIX2.21.1model refinement
20Coot0.9.8.94model refinement
CTF correctionType: NONE
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 177801 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeChain-IDInitial refinement model-ID
15JTW

5jtw

A5JTWA1
25JTW

5jtw

B5JTWB1
35JTW

5jtw

C5JTWC1
42ODP

2odp

E2ODPE
57B2Q

7b2q

D7B2QD3
62A73

2a73

F2A73F4
72A73

2a73

G2A73G4
RefinementHighest resolution: 3.5 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00330523
ELECTRON MICROSCOPYf_angle_d0.55141360
ELECTRON MICROSCOPYf_dihedral_angle_d5.6374356
ELECTRON MICROSCOPYf_chiral_restr0.0434670
ELECTRON MICROSCOPYf_plane_restr0.0045355

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