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- PDB-6rqj: Structure of human complement C5 complexed with tick inhibitors O... -

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Basic information

Entry
Database: PDB / ID: 6rqj
TitleStructure of human complement C5 complexed with tick inhibitors OmCI, RaCI1 and CirpT1
Components
  • (Complement C5Complement component 5) x 2
  • Complement inhibitor
  • Putative 8.9 kDa family member
  • Rhipicephalus appendiculatus RaCI1
KeywordsIMMUNOSUPPRESSANT / complement / inhibitor / innate immunity / inflammation / C5 / terminal pathway inhibitor
Function / homology
Function and homology information


Terminal pathway of complement / membrane attack complex / Activation of C3 and C5 / negative regulation of macrophage chemotaxis / complement activation, alternative pathway / chemokine activity / endopeptidase inhibitor activity / positive regulation of vascular endothelial growth factor production / complement activation, classical pathway / positive regulation of chemokine production ...Terminal pathway of complement / membrane attack complex / Activation of C3 and C5 / negative regulation of macrophage chemotaxis / complement activation, alternative pathway / chemokine activity / endopeptidase inhibitor activity / positive regulation of vascular endothelial growth factor production / complement activation, classical pathway / positive regulation of chemokine production / Peptide ligand-binding receptors / Regulation of Complement cascade / chemotaxis / G alpha (i) signalling events / toxin activity / killing of cells of another organism / cell surface receptor signaling pathway / inflammatory response / G protein-coupled receptor signaling pathway / signaling receptor binding / extracellular space / extracellular exosome / extracellular region
Similarity search - Function
Single domain Von Willebrand factor type C domain / Single domain von Willebrand factor type C / Single domain von Willebrand factor type C / : / Complement component 5, CUB domain / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / Anaphylatoxin domain signature. / Anaphylatoxin/fibulin ...Single domain Von Willebrand factor type C domain / Single domain von Willebrand factor type C / Single domain von Willebrand factor type C / : / Complement component 5, CUB domain / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / Anaphylatoxin domain signature. / Anaphylatoxin/fibulin / Anaphylatoxin, complement system / Anaphylotoxin-like domain / Anaphylatoxin domain profile. / Anaphylatoxin homologous domain / Netrin C-terminal Domain / Netrin module, non-TIMP type / UNC-6/NTR/C345C module / Netrin domain / NTR domain profile. / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG4 / Macroglobulin domain MG3 / A-macroglobulin receptor binding domain / Macroglobulin domain MG4 / 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 / Calycin beta-barrel core domain / Calycin / Lipocalin / Immunoglobulin-like fold / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Complement inhibitor RaCI1 / Complement inhibitor RaCI1 / Complement inhibitor CirpT1 / Complement C5 / Complement inhibitor
Similarity search - Component
Biological speciesRhipicephalus pulchellus (arthropod)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsReichhardt, M.P. / Johnson, S. / Lea, S.M.
Funding support Finland, United Kingdom, 4items
OrganizationGrant numberCountry
Finnish Cultural Foundation Finland
Wellcome Trust100298 United Kingdom
Wellcome Trust201536 United Kingdom
Wolfson FoundationWL160052 United Kingdom
CitationJournal: Proc Natl Acad Sci U S A / Year: 2020
Title: An inhibitor of complement C5 provides structural insights into activation.
Authors: Martin P Reichhardt / Steven Johnson / Terence Tang / Thomas Morgan / Nchimunya Tebeka / Niko Popitsch / Justin C Deme / Matthijs M Jore / Susan M Lea /
Abstract: The complement system is a crucial part of innate immune defenses against invading pathogens. The blood-meal of the tick lasts for days, and the tick must therefore rely on inhibitors to counter ...The complement system is a crucial part of innate immune defenses against invading pathogens. The blood-meal of the tick lasts for days, and the tick must therefore rely on inhibitors to counter complement activation. We have identified a class of inhibitors from tick saliva, the CirpT family, and generated detailed structural data revealing their mechanism of action. We show direct binding of a CirpT to complement C5 and have determined the structure of the C5-CirpT complex by cryoelectron microscopy. This reveals an interaction with the peripheral macro globulin domain 4 (C5_MG4) of C5. To achieve higher resolution detail, the structure of the C5_MG4-CirpT complex was solved by X-ray crystallography (at 2.7 Å). We thus present the fold of the CirpT protein family, and provide detailed mechanistic insights into its inhibitory function. Analysis of the binding interface reveals a mechanism of C5 inhibition, and provides information to expand our biological understanding of the activation of C5, and thus the terminal complement pathway.
History
DepositionMay 15, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 8, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2020Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name
Revision 1.2Jan 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_PDB_caveat / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_validate_chiral / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _chem_comp.name / _chem_comp.type / _database_PDB_caveat.text / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_chiral.auth_asym_id / _pdbx_validate_chiral.auth_seq_id / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

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Assembly

Deposited unit
A: Complement C5
C: Complement inhibitor
D: Rhipicephalus appendiculatus RaCI1
B: Complement C5
E: Putative 8.9 kDa family member
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,7996
Polymers225,3745
Non-polymers4241
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area15270 Å2
ΔGint-67 kcal/mol
Surface area82260 Å2
MethodPISA

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Components

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Protein , 5 types, 5 molecules ACDBE

#1: Protein Complement C5 / Complement component 5 / C3 and PZP-like alpha-2-macroglobulin domain-containing protein 4


Mass: 112635.008 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P01031
#2: Protein Complement inhibitor


Mass: 18647.588 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rhipicephalus pulchellus (arthropod) / Production host: Kluyveromyces lactis (yeast) / References: UniProt: Q5YD59
#3: Protein Rhipicephalus appendiculatus RaCI1


Mass: 8576.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rhipicephalus pulchellus (arthropod) / Production host: Escherichia coli (E. coli) / References: UniProt: A0A158RFT5, UniProt: A0A141SFN4*PLUS
#4: Protein Complement C5 / Complement component 5 / C3 and PZP-like alpha-2-macroglobulin domain-containing protein 4


Mass: 73361.453 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P01031
#5: Protein Putative 8.9 kDa family member


Mass: 12153.626 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rhipicephalus pulchellus (arthropod) / Production host: Escherichia coli (E. coli) / References: UniProt: L7MB58

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Sugars , 1 types, 1 molecules

#6: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-GlcpNAc]{}}}LINUCSPDB-CARE

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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
1Quaternary complex of human complement C5 with tick inhibitors OmCI, RaCI and CirpT1COMPLEX#1-#50MULTIPLE SOURCES
2Human Complement C5 (2)COMPLEX#1, #41NATURAL
3Complement inhibitorCOMPLEX#21RECOMBINANT
4Rhipicephalus appendiculatus RaCI1COMPLEX#31RECOMBINANT
5Putative 8.9 kDa family memberCOMPLEX#51RECOMBINANT
Molecular weightValue: 0.215 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Ornithodoros moubata (arthropod)6938
34Rhipicephalus appendiculatus (arthropod)34631
45Rhipicephalus pulchellus (arthropod)72859
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
13Kluyveromyces lactis (yeast)28985
24Escherichia coli (E. coli)562
35Escherichia coli (E. coli)562
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1137 mMsodium chlorideNaClSodium chloride1
22.7 mMpotassium chlorideKCl1
310 mMphosphatePO41
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 FIELDBright-field microscopy / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 8 sec. / Electron dose: 48 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 4440
Image scansMovie frames/image: 20

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Processing

Software
NameVersionClassificationNB
PHENIX1.15.1_3469refinement
PHENIX1.15.1_3469refinement
EM software
IDNameVersionCategory
1SIMPLEparticle selection
4CTFFIND4.1.8CTF correction
7Cootmodel fitting
9RELION3initial Euler assignment
10RELION3final Euler assignment
11RELION2.1classification
12RELION33D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 502640
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118634 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building
IDPDB-IDPdb chain-ID 3D fitting-ID
15HCE

5hce

1
26RPT

6rpt

B1
RefinementHighest resolution: 3.5 Å
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2

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