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- PDB-7akv: The cryo-EM structure of the Vag8-C1 inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 7akv
TitleThe cryo-EM structure of the Vag8-C1 inhibitor complex
Components
  • Plasma protease C1 inhibitor
  • Vag8
KeywordsPROTEIN BINDING / complex bacterial protein human protein immune system inhibitor
Function / homology
Function and homology information


negative regulation of complement activation, lectin pathway / Defective SERPING1 causes hereditary angioedema / outer membrane / blood circulation / complement activation, classical pathway / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / platelet alpha granule lumen / Regulation of Complement cascade / serine-type endopeptidase inhibitor activity ...negative regulation of complement activation, lectin pathway / Defective SERPING1 causes hereditary angioedema / outer membrane / blood circulation / complement activation, classical pathway / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / platelet alpha granule lumen / Regulation of Complement cascade / serine-type endopeptidase inhibitor activity / blood coagulation / Platelet degranulation / collagen-containing extracellular matrix / blood microparticle / endoplasmic reticulum lumen / innate immune response / extracellular space / extracellular exosome / extracellular region
Similarity search - Function
Pertactin virulence factor family / Pertactin, central region / Pertactin / Autotransporter beta-domain / Outer membrane autotransporter barrel / Autotransporter beta-domain / Autotransporter beta-domain profile. / Autotransporter beta-domain / Autotransporter beta-domain superfamily / Autotransporter, pectate lyase C-like domain superfamily ...Pertactin virulence factor family / Pertactin, central region / Pertactin / Autotransporter beta-domain / Outer membrane autotransporter barrel / Autotransporter beta-domain / Autotransporter beta-domain profile. / Autotransporter beta-domain / Autotransporter beta-domain superfamily / Autotransporter, pectate lyase C-like domain superfamily / Serpin, conserved site / Serpins signature. / Serpin superfamily, domain 2 / Serpin family / Serpin domain / Serpin superfamily / Serpin superfamily, domain 1 / Serpin (serine protease inhibitor) / SERine Proteinase INhibitors / Pectin lyase fold/virulence factor
Similarity search - Domain/homology
Vag8 / Plasma protease C1 inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human)
Bordetella pertussis (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsJohnson, S. / Lea, S.M. / Deme, J.C. / Furlong, E. / Dhillon, A.
Funding support United Kingdom, 4items
OrganizationGrant numberCountry
Wellcome Trust100298 United Kingdom
Wellcome Trust209194 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/M011984/1 United Kingdom
Wellcome Trust219477 United Kingdom
CitationJournal: mBio / Year: 2021
Title: Molecular Basis for Bordetella pertussis Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex.
Authors: Arun Dhillon / Justin C Deme / Emily Furlong / Dorina Roem / Ilse Jongerius / Steven Johnson / Susan M Lea /
Abstract: Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key ...Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-associated gene 8 (Vag8), produced by the whooping cough pathogen, , was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8-C1-INH complex determined using cryo-electron microscopy at a 3.6-Å resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases. The structure of a 10-kDa protein complex is one of the smallest to be determined using cryo-electron microscopy at high resolution. The structure reveals that C1-INH is sequestered in an inactivated state by burial of the reactive center loop in Vag8. By so doing, the bacterium is able to simultaneously perturb the many pathways regulated by C1-INH. Virulence mechanisms such as the one described here assume more importance given the emerging evidence about dysregulation of contact activation, coagulation, and fibrinolysis leading to COVID-19 pneumonia.
History
DepositionOct 2, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 16, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Plasma protease C1 inhibitor
G: Vag8


Theoretical massNumber of molelcules
Total (without water)136,2742
Polymers136,2742
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area1720 Å2
ΔGint-9 kcal/mol
Surface area30300 Å2
MethodPISA

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Components

#1: Protein Plasma protease C1 inhibitor / C1 Inh / C1Inh / C1 esterase inhibitor / C1-inhibiting factor / Serpin G1


Mass: 45011.637 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SERPING1, C1IN, C1NH / Production host: Drosophila albipalpis (fry) / References: UniProt: P05155
#2: Protein Vag8


Mass: 91262.172 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bordetella pertussis (bacteria) / Gene: vag-8 / Production host: Escherichia coli (E. coli) / References: UniProt: O66044

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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: Vag8:C1 inhibitor complex / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightValue: 0.1 MDa / Experimental value: NO
Buffer solutionpH: 8
SpecimenEmbedding 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 FIELDBright-field microscopy
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refinedev_3928refinement
PHENIXdev_3928refinement
EM software
IDNameVersionCategory
1SIMPLE3particle selection
4SIMPLE3CTF correction
9SIMPLE3initial Euler assignment
10RELION3.1final Euler assignment
12RELION3.13D reconstruction
13PHENIXdev-3965model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 17261358
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 687883 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 103.34 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00356053
ELECTRON MICROSCOPYf_angle_d0.60098222
ELECTRON MICROSCOPYf_chiral_restr0.0417986
ELECTRON MICROSCOPYf_plane_restr0.00411066
ELECTRON MICROSCOPYf_dihedral_angle_d10.4248839

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