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- PDB-6rpt: Structure of tick complement inhibitor CirpT1 complexed with macr... -

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Basic information

Entry
Database: PDB / ID: 6rpt
TitleStructure of tick complement inhibitor CirpT1 complexed with macroglobubulin domain 4 of human complement C5
Components
  • Complement C5
  • Putative 8.9 kDa family member
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 / killing of cells of another organism / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / inflammatory response / 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, complement system ...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, 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 / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / Immunoglobulin-like fold / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Complement inhibitor CirpT1 / Complement C5
Similarity search - Component
Biological speciesHomo sapiens (human)
Rhipicephalus pulchellus (arthropod)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsReichhardt, M.P. / Lea, S.M. / Johnson, S.
Funding support Finland, United Kingdom, 2items
OrganizationGrant numberCountry
Finnish Cultural Foundation Finland
Wellcome Trust100298 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 14, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 8, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
E: Complement C5
F: Putative 8.9 kDa family member
A: Complement C5
B: Putative 8.9 kDa family member
C: Complement C5
D: Putative 8.9 kDa family member
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,84911
Polymers80,3896
Non-polymers4605
Water1,982110
1
E: Complement C5
F: Putative 8.9 kDa family member
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,9804
Polymers26,7962
Non-polymers1842
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2140 Å2
ΔGint-5 kcal/mol
Surface area11050 Å2
MethodPISA
2
A: Complement C5
B: Putative 8.9 kDa family member
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,9804
Polymers26,7962
Non-polymers1842
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2150 Å2
ΔGint-9 kcal/mol
Surface area11180 Å2
MethodPISA
3
C: Complement C5
D: Putative 8.9 kDa family member
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,8883
Polymers26,7962
Non-polymers921
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1910 Å2
ΔGint-7 kcal/mol
Surface area11150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.830, 56.948, 90.072
Angle α, β, γ (deg.)90.000, 113.020, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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


Mass: 14511.433 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: C5, CPAMD4 / Production host: Escherichia coli (E. coli) / References: UniProt: P01031
#2: Protein Putative 8.9 kDa family member


Mass: 12284.823 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rhipicephalus pulchellus (arthropod) / Production host: Escherichia coli (E. coli) / References: UniProt: L7MB58
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 110 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.55 Å3/Da / Density % sol: 51.76 %
Crystal growTemperature: 284.15 K / Method: vapor diffusion, sitting drop / Details: 0.02 M Na2PO4/K2PO4, 20 % w/v PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9762 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 8, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2.52→82.9 Å / Num. obs: 22552 / % possible obs: 99.8 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.266 / Net I/σ(I): 3.8
Reflection shellResolution: 2.52→2.56 Å / Num. unique obs: 2243

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Processing

Software
NameVersionClassification
PHENIXdev_3126refinement
DIALSxia2 Dialsdata reduction
DIALSxia2 Dialsdata scaling
MOLREPCCP4Interface 7.0.056phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5HCC

5hcc


Resolution: 2.7→82.9 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.272 --
Rwork0.226 --
obs-22549 99.8 %
Refinement stepCycle: LAST / Resolution: 2.7→82.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4518 0 30 110 4658

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