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- EMDB-41710: Cryo-EM structure of coagulation factor VIII bound to NB2E9 -

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Basic information

Entry
Database: EMDB / ID: EMD-41710
TitleCryo-EM structure of coagulation factor VIII bound to NB2E9
Map data
Sample
  • Complex: Coagulation factor VIII bound to NB2E9
    • Protein or peptide: Coagulation factor VIII
    • Protein or peptide: NB2E9 light chain
    • Protein or peptide: NB2E9 heavy chain
KeywordsCoagulation / Inhibitor antibody / factor VIII / BLOOD CLOTTING-INHIBITOR 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 / Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation / Defective F8 sulfation at Y1699 / 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 / Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation / Defective F8 sulfation at Y1699 / 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-mediated vesicle transport / COPII-coated ER to Golgi transport vesicle / 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 / signaling receptor activity / oxidoreductase activity / copper ion binding / endoplasmic reticulum lumen / 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 / F5/8 type C domain ...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
Similarity search - Domain/homology
Coagulation factor VIII / Coagulation factor VIII
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.46 Å
AuthorsChilders KC / Spiegel PC
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL141981 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL135658 United States
CitationJournal: To Be Published
Title: Structural basis for inhibition of coagulation factor VIII reveals a shared immunogenic hot-spot on the C1 domain
Authors: Childers KC / Vaughan J / McGill J / Davulcu O / Lollar P / Doering CB / Coxon CH / Spiegel PC
History
DepositionAug 24, 2023-
Header (metadata) releaseSep 13, 2023-
Map releaseSep 13, 2023-
UpdateSep 13, 2023-
Current statusSep 13, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41710.png

Downloads & links

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Map

FileDownload / File: emd_41710.map.gz / Format: CCP4 / Size: 600.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.788 Å
Density
Contour LevelBy AUTHOR: 0.0443
Minimum - Maximum-0.39161098 - 0.6920698
Average (Standard dev.)-0.0002493059 (±0.0074400897)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions540540540
Spacing540540540
CellA=B=C: 425.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_41710_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_41710_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Coagulation factor VIII bound to NB2E9

EntireName: Coagulation factor VIII bound to NB2E9
Components
  • Complex: Coagulation factor VIII bound to NB2E9
    • Protein or peptide: Coagulation factor VIII
    • Protein or peptide: NB2E9 light chain
    • Protein or peptide: NB2E9 heavy chain

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Supramolecule #1: Coagulation factor VIII bound to NB2E9

SupramoleculeName: Coagulation factor VIII bound to NB2E9 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Coagulation factor VIII

MacromoleculeName: Coagulation factor VIII / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 168.287047 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: MQLELSTCVF LCLLPLGFSA IRRYYLGAVE LSWDYRQSEL LRELHVDTRF PATAPGALPL GPSVLYKKTV FVEFTDQLFS VARPRPPWM GLLGPTIQAE VYDTVVVTLK NMASHPVSLH AVGVSFWKSS EGAEYEDHTS QREKEDDKVL PGKSQTYVWQ V LKENGPTA ...String:
MQLELSTCVF LCLLPLGFSA IRRYYLGAVE LSWDYRQSEL LRELHVDTRF PATAPGALPL GPSVLYKKTV FVEFTDQLFS VARPRPPWM GLLGPTIQAE VYDTVVVTLK NMASHPVSLH AVGVSFWKSS EGAEYEDHTS QREKEDDKVL PGKSQTYVWQ V LKENGPTA SDPPCLTYSY LSHVDLVKDL NSGLIGALLV CREGSLTRER TQNLHEFVLL FAVFDEGKSW HSARNDSWTR AM DPAPARA QPAMHTVNGY VNRSLPGLIG CHKKSVYWHV IGMGTSPEVH SIFLEGHTFL VRHHRQASLE ISPLTFLTAQ TFL MDLGQF LLFCHISSHH HGGMEAHVRV ESCAEEPQLR RKADEEEDYD DNLYDSDMDV VRLDGDDVSP FIQIRSVAKK HPKT WVHYI AAEEEDWDYA PLVLAPDDRS YKSQYLNNGP QRIGRKYKKV RFMAYTDETF KTREAIQHES GILGPLLYGE VGDTL LIIF KNQASRPYNI YPHGITDVRP LYSRRLPKGV KHLKDFPILP GEIFKYKWTV TVEDGPTKSD PRCLTRYYSS FVNMER DLA SGLIGPLLIC YKESVDQRGN QIMSDKRNVI LFSVFDENRS WYLTENIQRF LPNPAGVQLE DPEFQASNIM HSINGYV FD SLQLSVCLHE VAYWYILSIG AQTDFLSVFF SGYTFKHKMV YEDTLTLFPF SGETVFMSME NPGLWILGCH NSDFRNRG M TALLKVSSCD KNTGDYYEDS YEDISAYLLS KNNAIEPRSF AQNSRPPSAS APKPPVLRRH QRDISLPTFQ PEEDKMDYD DIFSTETKGE DFDIYGEDEN QDPRSFQKRT RHYFIAAVEQ LWDYGMSESP RALRNRAQNG EVPRFKKVVF REFADGSFTQ PSYRGELNK HLGLLGPYIR AEVEDNIMVT FKNQASRPYS FYSSLISYPD DQEQGAEPRH NFVQPNETRT YFWKVQHHMA P TEDEFDCK AWAYFSDVDL EKDVHSGLIG PLLICRANTL NAAHGRQVTV QEFALFFTIF DETKSWYFTE NVERNCRAPC HL QMEDPTL KENYRFHAIN GYVMDTLPGL VMAQNQRIRW YLLSMGSNEN IHSIHFSGHV FSVRKKEEYK MAVYNLYPGV FET VEMLPS KVGIWRIECL IGEHLQAGMS TTFLVYSKKC QTPLGMASGH IRDFQITASG QYGQWAPKLA RLHYSGSINA WSTK EPFSW IKVDLLAPMI IHGIKTQGAR QKFSSLYISQ FIIMYSLDGK KWQTYRGNST GTLMVFFGNV DSSGIKHNIF NPPII ARYI RLHPTHYSIR STLRMELMGC DLNSCSMPLG MESKAISDAQ ITASSYFTNM FATWSPSKAR LHLQGRSNAW RPQVNN PKE WLQVDFQKTM KVTGVTTQGV KSLLTSMYVK EFLISSSQDG HQWTLFFQNG KVKVFQGNQD SFTPVVNSLD PPLLTRY LR IHPQSWVHQI ALRMEVLGCE AQDLY

UniProtKB: Coagulation factor VIII, Coagulation factor VIII, Coagulation factor VIII, Coagulation factor VIII

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Macromolecule #2: NB2E9 light chain

MacromoleculeName: NB2E9 light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.513164 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EIVLTQFPGT LSLSPGERAT LSCRASQSVA SAYLAWYQQK PGQAPRLLIY GASSRATDIP HRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGTSALLT FGGGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ ...String:
EIVLTQFPGT LSLSPGERAT LSCRASQSVA SAYLAWYQQK PGQAPRLLIY GASSRATDIP HRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGTSALLT FGGGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC

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Macromolecule #3: NB2E9 heavy chain

MacromoleculeName: NB2E9 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.373285 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVQSGAE VKKPGASVKV SCKTSGYNFT GYSASGHIFT AYSVHWVRQA PGQGLEWMGR INPNSGATDY AHKFQGRVTM SRDTSISTA YMELSRLTSD DTAMYYCARA DNYFDIVTGY TSHYFDYWGR GTLVTVSSAS TKGPSVFPLA PCSRSTSEST A ALGCLVKD ...String:
QVQLVQSGAE VKKPGASVKV SCKTSGYNFT GYSASGHIFT AYSVHWVRQA PGQGLEWMGR INPNSGATDY AHKFQGRVTM SRDTSISTA YMELSRLTSD DTAMYYCARA DNYFDIVTGY TSHYFDYWGR GTLVTVSSAS TKGPSVFPLA PCSRSTSEST A ALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY TCNVDHKPSN TKVDKRV

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.1 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chloridesodium chloride
20.0 mMC8H18N2O4SHEPES

Details: 20 mM HEPES (pH 7.4) and 150 mM NaCl
GridMesh: 400 / Support film - Material: CARBON / Support film - topology: LACEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.7 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6mf0

Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2.1)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 94935

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