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- PDB-7k66: Structure of Blood Coagulation Factor VIII in Complex with an Ant... -

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Basic information

Entry
Database: PDB / ID: 7k66
TitleStructure of Blood Coagulation Factor VIII in Complex with an Anti-C1 Domain Pathogenic Antibody Inhibitor
Components
  • 2A9 heavy chain
  • 2A9 light chain
  • Coagulation factor VIII,Coagulation factor VIII,Coagulation factor VIII,Coagulation factor VIII
KeywordsBLOOD CLOTTING/Immune System / Antibody / inhibitor / BLOOD CLOTTING / BLOOD CLOTTING-Immune System complex
Function / homology
Function and homology information


Defective F8 accelerates dissociation of the A2 domain / Defective F8 binding to the cell membrane / Defective F8 secretion / Defective F8 sulfation at Y1699 / Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation / Defective F8 binding to von Willebrand factor / blood coagulation, intrinsic pathway / Cargo concentration in the ER / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant ...Defective F8 accelerates dissociation of the A2 domain / Defective F8 binding to the cell membrane / Defective F8 secretion / Defective F8 sulfation at Y1699 / Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation / Defective F8 binding to von Willebrand factor / blood coagulation, intrinsic pathway / Cargo concentration in the ER / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / COPII-coated ER to Golgi transport vesicle / COPII-mediated vesicle transport / Defective F8 cleavage by thrombin / Common Pathway of Fibrin Clot Formation / Intrinsic Pathway of Fibrin Clot Formation / endoplasmic reticulum-Golgi intermediate compartment membrane / platelet alpha granule lumen / acute-phase response / Golgi lumen / blood coagulation / Platelet degranulation / oxidoreductase activity / endoplasmic reticulum lumen / copper ion binding / extracellular space / extracellular region / plasma membrane
Similarity search - Function
Coagulation factor 5/8-like / : / Coagulation factors 5/8 type C domain (FA58C) signature 2. / Multicopper oxidases, conserved site / Multicopper oxidases signature 1. / Coagulation factors 5/8 type C domain (FA58C) signature 1. / Coagulation factor 5/8 C-terminal domain, discoidin domain / Coagulation factors 5/8 type C domain (FA58C) profile. / Multicopper oxidase, C-terminal / Multicopper oxidase ...Coagulation factor 5/8-like / : / Coagulation factors 5/8 type C domain (FA58C) signature 2. / Multicopper oxidases, conserved site / Multicopper oxidases signature 1. / Coagulation factors 5/8 type C domain (FA58C) signature 1. / Coagulation factor 5/8 C-terminal domain, discoidin domain / Coagulation factors 5/8 type C domain (FA58C) profile. / Multicopper oxidase, C-terminal / Multicopper oxidase / F5/8 type C domain / Coagulation factor 5/8 C-terminal domain / Multicopper oxidase, type 1 / Multicopper oxidase / Multicopper oxidase, N-terminal / Multicopper oxidase / Cupredoxin / Galactose-binding-like domain superfamily / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
COPPER (II) ION / Coagulation factor VIII / Coagulation factor VIII
Similarity search - Component
Biological speciesSus scrofa (pig)
Homo sapiens (human)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.92 Å
AuthorsChilders, K.C. / Gish, J. / Jarvis, L. / Peters, S. / Garrels, C. / Smith, I.W. / Spencer, H.T. / Spiegel, P.C.
Funding support United States, 6items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)MRI 1429164 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R15HL103518 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)U54HL141981 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R44HL117511 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R44HL110448 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)U54HL112309 United States
CitationJournal: Blood / Year: 2021
Title: Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor.
Authors: Gish, J.S. / Jarvis, L. / Childers, K.C. / Peters, S.C. / Garrels, C.S. / Smith, I.W. / Spencer, H.T. / Doering, C.B. / Lollar, P. / Spiegel, P.C.
History
DepositionSep 18, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 14, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jun 9, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.3Oct 18, 2023Group: 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 1.4Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Coagulation factor VIII,Coagulation factor VIII,Coagulation factor VIII,Coagulation factor VIII
B: 2A9 heavy chain
C: 2A9 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)217,2909
Polymers215,5653
Non-polymers1,7256
Water181
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7550 Å2
ΔGint-10 kcal/mol
Surface area73990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)116.721, 116.721, 371.057
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Coagulation factor VIII,Coagulation factor VIII,Coagulation factor VIII,Coagulation factor VIII / Procoagulant component / Antihemophilic factor / AHF / Procoagulant component


Mass: 168287.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Sus scrofa (pig), (gene. exp.) Homo sapiens (human)
Gene: F8, CF8, F8, F8C / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P12263, UniProt: P00451

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Antibody , 2 types, 2 molecules BC

#2: Antibody 2A9 heavy chain


Mass: 23979.773 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
#3: Antibody 2A9 light chain


Mass: 23297.727 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)

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Sugars , 3 types, 3 molecules

#4: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#5: 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: 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.: 1 / 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

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Non-polymers , 4 types, 4 molecules

#7: Chemical ChemComp-CU / COPPER (II) ION


Mass: 63.546 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cu
#8: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#9: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
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: 2.99 Å3/Da / Density % sol: 58.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.7 / Details: 17.5 %(w/v) PEG 1500, 50 mM HEPES (pH 7.7)

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 28, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.92→49.49 Å / Num. obs: 23431 / % possible obs: 97.61 % / Redundancy: 2 % / Biso Wilson estimate: 147.58 Å2 / CC1/2: 0.994 / CC star: 0.999 / Rmerge(I) obs: 0.09953 / Net I/σ(I): 5.74
Reflection shellResolution: 3.92→4.06 Å / Redundancy: 2 % / Rmerge(I) obs: 0.9323 / Num. unique obs: 2201 / CC1/2: 0.342 / CC star: 0.714 / % possible all: 94.06

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Processing

Software
NameVersionClassification
Adxvdata reduction
XDSdata reduction
PHASERphasing
Cootmodel building
PHENIX1.18.2-3874refinement
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6MF0

6mf0


Resolution: 3.92→49.49 Å / SU ML: 0.7741 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 33.7576
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3219 1991 8.5 %
Rwork0.2257 21440 -
obs0.2341 23431 97.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 148.55 Å2
Refinement stepCycle: LAST / Resolution: 3.92→49.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13500 0 106 1 13607

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