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- PDB-8oq3: Structure of methylamine treated human complement C3 -

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Basic information

Entry
Database: PDB / ID: 8oq3
TitleStructure of methylamine treated human complement C3
Components
  • Complement C3
  • nanobody hC3Nb1 with mutation
KeywordsIMMUNE SYSTEM / innate immune system / complement / activation / nanobody
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 speciesLama glama (llama)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsGadeberg, T.A.F. / Andersen, G.R.
Funding support Denmark, 3items
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, 2023Deposition site: PDBE / Processing site: PDBE
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Complement C3
C: nanobody hC3Nb1 with mutation
D: Complement C3
F: nanobody hC3Nb1 with mutation
hetero molecules


Theoretical massNumber of molelcules
Total (without water)400,3708
Polymers398,7544
Non-polymers1,6164
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area8580 Å2
ΔGint10 kcal/mol
Surface area140050 Å2

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Components

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


Mass: 185173.281 Da / Num. of mol.: 2 / Source method: isolated from a natural source
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
Source: (natural) Homo sapiens (human) / References: UniProt: P01024
#2: Antibody nanobody hC3Nb1 with mutation


Mass: 14203.742 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#3: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#4: 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.: 2 / 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
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

Component
IDNameTypeEntity IDParent-IDSource
1methylamine treated complement C3 in complex with a nanobody enabling dimer formationCOMPLEX#1-#20NATURAL
2nanobody hC3Nb1 with mutationCOMPLEX#21NATURAL
3complement C3COMPLEX#11NATURAL
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.2 MDaYES
210.015 MDaYES
310.185 MDaYES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Lama glama (llama)9844
43Homo sapiens (human)9606
Buffer solutionpH: 7
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2438 nm / Nominal defocus min: 170 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 59.5 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 197438 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00727134
ELECTRON MICROSCOPYf_angle_d1.13336792
ELECTRON MICROSCOPYf_dihedral_angle_d6.4263684
ELECTRON MICROSCOPYf_chiral_restr0.0634172
ELECTRON MICROSCOPYf_plane_restr0.0084754

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