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- PDB-9qj4: Structure of the Complement classical and lectin pathway proconve... -

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Basic information

Entry
Database: PDB / ID: 9qj4
TitleStructure of the Complement classical and lectin pathway proconvertase, C4b2
Components
  • Complement C2
  • Complement C4-A
KeywordsIMMUNE SYSTEM / Proconvertase / Complement / classical pathway / C4b2
Function / homology
Function and homology information


classical-complement-pathway C3/C5 convertase / complement component C1q complex binding / response to thyroid hormone / positive regulation of apoptotic cell clearance / Activation of C3 and C5 / complement activation, GZMK pathway / symbiont cell surface / complement activation / Initial triggering of complement / endopeptidase inhibitor activity ...classical-complement-pathway C3/C5 convertase / complement component C1q complex binding / response to thyroid hormone / positive regulation of apoptotic cell clearance / Activation of C3 and C5 / complement activation, GZMK pathway / symbiont cell surface / complement activation / Initial triggering of complement / endopeptidase inhibitor activity / complement activation, classical pathway / response to nutrient / Regulation of Complement cascade / Post-translational protein phosphorylation / response to bacterium / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / blood microparticle / response to lipopolysaccharide / endoplasmic reticulum lumen / inflammatory response / serine-type endopeptidase activity / axon / neuronal cell body / synapse / dendrite / cell surface / 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 / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Anaphylatoxin, complement system domain / : / Alpha-macro-globulin thiol-ester bond-forming region ...: / : / Complement C4, MG1 domain / Complement C4A/B CUB C-terminal domain / Complement B/C2 / 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 C2 / Complement C4-A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 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 18, 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
B: Complement C4-A
D: Complement C2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)663,0738
Polymers662,3854
Non-polymers6884
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

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


Mass: 193007.234 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: 83363.766 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: blood plasma
References: UniProt: P06681, classical-complement-pathway C3/C5 convertase
#3: 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.: 3 / 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
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
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 proconvertase / Type: COMPLEX / Entity ID: #1-#2 / Source: NATURAL
Molecular weightValue: 0.288 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
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Complex was crosslinked with glutaraldehyde 0.2%
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

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 2.24 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4662

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Processing

EM software
IDNameVersionCategory
1cryoSPARCv3.2/3particle selection
2EPU2.10.0image acquisition
4cryoSPARCv3.2/3CTF correction
7UCSF ChimeraX1.7model fitting
9cryoSPARCv3.2/3initial Euler assignment
10cryoSPARCv3.2/3final Euler assignment
11cryoSPARCv3.2/3classification
12cryoSPARCv3.2/33D reconstruction
19PHENIX2.21.1model refinement
20Coot0.9.8.94model refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 2647189
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 31895 / Num. of class averages: 3 / 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
43ERB

3erb

D3ERBD2
52I6Q

2i6q

D2I6QD
RefinementHighest resolution: 3.9 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00415613
ELECTRON MICROSCOPYf_angle_d0.82721182
ELECTRON MICROSCOPYf_dihedral_angle_d5.5482196
ELECTRON MICROSCOPYf_chiral_restr0.0472343
ELECTRON MICROSCOPYf_plane_restr0.0052763

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