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- EMDB-17103: Structure of methylamine treated human complement C3 -

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Basic information

Entry
Database: EMDB / ID: EMD-17103
TitleStructure of methylamine treated human complement C3
Map datafull map of methylamine treated C3
Sample
  • Complex: methylamine treated complement C3 in complex with a nanobody enabling dimer formation
    • Complex: nanobody hC3Nb1 with mutation
      • Protein or peptide: nanobody hC3Nb1 with mutation
    • Complex: complement C3
      • Protein or peptide: Complement C3
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsinnate immune system / complement / activation / nanobody / IMMUNE SYSTEM
Function / homology
Function and homology information


C5L2 anaphylatoxin chemotactic receptor binding / oviduct epithelium development / regulation of triglyceride biosynthetic process / positive regulation of activation of membrane attack complex / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / complement-mediated synapse pruning / Alternative complement activation / Activation of C3 and C5 / positive regulation of phagocytosis, engulfment ...C5L2 anaphylatoxin chemotactic receptor binding / oviduct epithelium development / regulation of triglyceride biosynthetic process / positive regulation of activation of membrane attack complex / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / complement-mediated synapse pruning / Alternative complement activation / Activation of C3 and C5 / positive regulation of phagocytosis, engulfment / positive regulation of lipid storage / positive regulation of G protein-coupled receptor signaling pathway / complement receptor mediated signaling pathway / positive regulation of type IIa hypersensitivity / complement-dependent cytotoxicity / positive regulation of D-glucose transmembrane transport / complement activation / complement activation, alternative pathway / endopeptidase inhibitor activity / neuron remodeling / amyloid-beta clearance / B cell activation / positive regulation of vascular endothelial growth factor production / complement activation, classical pathway / Purinergic signaling in leishmaniasis infection / Peptide ligand-binding receptors / Regulation of Complement cascade / fatty acid metabolic process / Post-translational protein phosphorylation / response to bacterium / positive regulation of receptor-mediated endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of angiogenesis / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / azurophil granule lumen / positive regulation of protein phosphorylation / G alpha (i) signalling events / secretory granule lumen / blood microparticle / immune response / G protein-coupled receptor signaling pathway / inflammatory response / receptor ligand activity / endoplasmic reticulum lumen / signaling receptor binding / Neutrophil degranulation / cell surface / signal transduction / protein-containing complex / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain ...Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / : / Anaphylatoxin domain signature. / Alpha-macro-globulin thiol-ester bond-forming region / 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 / Netrin domain / NTR domain profile. / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain / Macroglobulin domain MG3 / A-macroglobulin receptor / Tissue inhibitor of metalloproteinases-like, OB-fold / Alpha-2-macroglobulin / Macroglobulin domain / 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 / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / Immunoglobulin-like fold
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsGadeberg TAF / Andersen GR
Funding support Denmark, 3 items
OrganizationGrant numberCountry
LundbeckfondenR155-2015-2666 Denmark
Novo Nordisk FoundationNNF18OC0052105 Denmark
Danish Council for Independent Research4181-00137B Denmark
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring.
Authors: Trine Amalie Fogh Gadeberg / Martin Høgholm Jørgensen / Heidi Gytz Olesen / Josefine Lorentzen / Seandean Lykke Harwood / Ana Viana Almeida / Marlene Uglebjerg Fruergaard / Rasmus Kjeldsen ...Authors: Trine Amalie Fogh Gadeberg / Martin Høgholm Jørgensen / Heidi Gytz Olesen / Josefine Lorentzen / Seandean Lykke Harwood / Ana Viana Almeida / Marlene Uglebjerg Fruergaard / Rasmus Kjeldsen Jensen / Philipp Kanis / Henrik Pedersen / Emil Tranchant / Steen Vang Petersen / Ida Buch Thøgersen / Birthe Brandt Kragelund / Joseph Anthony Lyons / Jan Johannes Enghild / Gregers Rom Andersen /
Abstract: The C3 protein is the central molecule within the complement system and undergoes proteolytic activation to C3b in the presence of pathogens. Pattern-independent activation of C3 also occurs via ...The C3 protein is the central molecule within the complement system and undergoes proteolytic activation to C3b in the presence of pathogens. Pattern-independent activation of C3 also occurs via hydrolysis, resulting in C3(HO), but the structural details of C3 hydrolysis remain elusive. Here we show that the conformation of the C3(HO) analog, C3MA, is indistinguishable from C3b. In contrast, the reaction intermediate C3* adopts a conformation dramatically different from both C3 and C3MA. In C3*, unlocking of the macroglobulin (MG) 3 domain creates a large opening in the MG ring through which the anaphylatoxin (ANA) domain translocates through a transient opening. C3MA formation is inhibited by an MG3-specific nanobody and prevented by linking the ANA domain to the C3 β-chain. Our study reveals an unexpected dynamic behavior of C3 and forms the basis for elucidation of the in vivo contribution of C3 hydrolysis and for controlling complement upon intravascular hemolysis and surface-contact-induced activation.
History
DepositionApr 11, 2023-
Header (metadata) releaseFeb 21, 2024-
Map releaseFeb 21, 2024-
UpdateMar 5, 2025-
Current statusMar 5, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17103.png

Downloads & links

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Map

FileDownload / File: emd_17103.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationfull map of methylamine treated C3
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 480 pix.
= 310.56 Å		0.65 Å/pix.
x 480 pix.
= 310.56 Å		0.65 Å/pix.
x 480 pix.
= 310.56 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.647 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025
Minimum - Maximum-0.14612345 - 0.27055904
Average (Standard dev.)0.00023026997 (±0.0077695367)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 310.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map A of methylamine treated C3

Fileemd_17103_half_map_1.map
Annotationhalf map A of methylamine treated C3
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_17103_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : methylamine treated complement C3 in complex with a nanobody enab...

EntireName: methylamine treated complement C3 in complex with a nanobody enabling dimer formation
Components
  • Complex: methylamine treated complement C3 in complex with a nanobody enabling dimer formation
    • Complex: nanobody hC3Nb1 with mutation
      • Protein or peptide: nanobody hC3Nb1 with mutation
    • Complex: complement C3
      • Protein or peptide: Complement C3
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: methylamine treated complement C3 in complex with a nanobody enab...

SupramoleculeName: methylamine treated complement C3 in complex with a nanobody enabling dimer formation
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 185 KDa

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Supramolecule #2: nanobody hC3Nb1 with mutation

SupramoleculeName: nanobody hC3Nb1 with mutation / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Lama glama (llama)

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Supramolecule #3: complement C3

SupramoleculeName: complement C3 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Complement C3

MacromoleculeName: Complement C3 / type: protein_or_peptide / ID: 1
Details: this is a two chain protein, see uniprot entry co3_human. Compared to this entry, the signal peptide is missing and furin cleavage has removed residues 668-671. the remaining residues are in ...Details: this is a two chain protein, see uniprot entry co3_human. Compared to this entry, the signal peptide is missing and furin cleavage has removed residues 668-671. the remaining residues are in the molecule but not modelled
Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 185.173281 KDa
SequenceString: SPMYSIITPN ILRLESEETM VLEAHDAQGD VPVTVTVHDF PGKKLVLSSE KTVLTPATNH MGNVTFTIPA NREFKSEKGR NKFVTVQAT FGTQVVEKVV LVSLQSGYLF IQTDKTIYTP GSTVLYRIFT VNHKLLPVGR TVMVNIENPE GIPVKQDSLS S QNQLGVLP ...String:
SPMYSIITPN ILRLESEETM VLEAHDAQGD VPVTVTVHDF PGKKLVLSSE KTVLTPATNH MGNVTFTIPA NREFKSEKGR NKFVTVQAT FGTQVVEKVV LVSLQSGYLF IQTDKTIYTP GSTVLYRIFT VNHKLLPVGR TVMVNIENPE GIPVKQDSLS S QNQLGVLP LSWDIPELVN MGQWKIRAYY ENSPQQVFST EFEVKEYVLP SFEVIVEPTE KFYYIYNEKG LEVTITARFL YG KKVEGTA FVIFGIQDGE QRISLPESLK RIPIEDGSGE VVLSRKVLLD GVQNPRAEDL VGKSLYVSAT VILHSGSDMV QAE RSGIPI VTSPYQIHFT KTPKYFKPGM PFDLMVFVTN PDGSPAYRVP VAVQGEDTVQ SLTQGDGVAK LSINTHPSQK PLSI TVRTK KQELSEAEQA TRTMQALPYS TVGNSNNYLH LSVLRTELRP GETLNVNFLL RMDRAHEAKI RYYTYLIMNK GRLLK AGRQ VREPGQDLVV LPLSITTDFI PSFRLVAYYT LIGASGQREV VADSVWVDVK DSCVGSLVVK SGQSEDRQPV PGQQMT LKI EGDHGARVVL VAVDKGVFVL NKKNKLTQSK IWDVVEKADI GCTPGSGKDY AGVFSDAGLT FTSSSGQQTA QRAELQC PQ PAARRRRSVQ LTEKRMDKVG KYPKELRKCC EDGMRENPMR FSCQRRTRFI SLGEACKKVF LDCCNYITEL RRQHARAS H LGLARSNLDE DIIAEENIVS RSEFPESWLW NVEDLKEPPK NGISTKLMNI FLKDSITTWE ILAVSMSDKK GICVADPFE VTVMQDFFID LRLPYSVVRN EQVEIRAVLY NYRQNQELKV RVELLHNPAF CSLATTKRRH QQTVTIPPKS SLSVPYVIVP LKTGLQEVE VKAAVYHHFI SDGVRKSLKV VPEGIRMNKT VAVRTLDPER LGREGVQKED IPPADLSDQV PDTESETRIL L QGTPVAQM TEDAVDAERL KHLIVTPSGC GEQNMIGMTP TVIAVHYLDE TEQWEKFGLE KRQGALELIK KGYTQQLAFR QP SSAFAAF VKRAPSTWLT AYVVKVFSLA VNLIAIDSQV LCGAVKWLIL EKQKPDGVFQ EDAPVIHQEM IGGLRNNNEK DMA LTAFVL ISLQEAKDIC EEQVNSLPGS ITKAGDFLEA NYMNLQRSYT VAIAGYALAQ MGRLKGPLLN KFLTTAKDKN RWED PGKQL YNVEATSYAL LALLQLKDFD FVPPVVRWLN EQRYYGGGYG STQATFMVFQ ALAQYQKDAP DHQELNLDVS LQLPS RSSK ITHRIHWESA SLLRSEETKE NEGFTVTAEG KGQGTLSVVT MYHAKAKDQL TCNKFDLKVT IKPAPETEKR PQDAKN TMI LEICTRYRGD QDATMSILDI SMMTGFAPDT DDLKQLANGV DRYISKYELD KAFSDRNTLI IYLDKVSHSE DDCLAFK VH QYFNVELIQP GAVKVYAYYN LEESCTRFYH PEKEDGKLNK LCRDELCRCA EENCFIQKSD DKVTLEERLD KACEPGVD Y VYKTRLVKVQ LSNDFDEYIM AIEQTIKSGS DEVQVGQQRT FISPIKCREA LKLEEKKHYL MWGLSSDFWG EKPNLSYII GKDTWVEHWP EEDECQDEEN QKQCQDLGAF TESMVVFGCP N

UniProtKB: Complement C3

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Macromolecule #2: nanobody hC3Nb1 with mutation

MacromoleculeName: nanobody hC3Nb1 with mutation / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 14.203742 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLVETGGG LVQAGGSLRL SCAASGSIFS INAMGWFRQA PGKEREFVAT INRSGGRTYY ADSVKGRFTI SRDNGKNMVY LQMHSLKPE DTAIYYCAAG TGWSPQTDCE YNYWGQGTQV TVSSHHHHHH

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.0 mg/mL
BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 59.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.438 µm / Nominal defocus min: 0.17 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 197438
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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