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- EMDB-76484: Structural determination of lipid-bound Factor VIII -

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Basic information

Entry
Database: EMDB / ID: EMD-76484
TitleStructural determination of lipid-bound Factor VIII
Map data
Sample
  • Complex: Coagulation Factor VIII
KeywordsCoagulation / Intrinsic Pathway / Hemophilia / Factor VIII / BLOOD CLOTTING
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.46 Å
AuthorsMohammed BM
Funding support United States, 5 items
OrganizationGrant numberCountry
Other privateDoisy Fund of the Edward A. Doisy Department of Biochemistry and Molecular Biology United States
Childrens Discovery Institute of Washington University and St. Louis Childrens HospitalCDI-CORE-2015-505 and CDI-CORE-2019-813 United States
The Foundation for Barnes-Jewish Hospital3770 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK020579 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA091842 United States
CitationJournal: J Thromb Haemost / Year: 2026
Title: Structural determination of lipid-bound Factor VIII.
Authors: Bassem M Mohammed
Abstract: BACKGROUND: Coagulation factor (F)VIII is the inactive precursor of FVIIIa, an essential component of the intrinsic tenase complex. Despite numerous structures of recombinant FVIII in solution, the ...BACKGROUND: Coagulation factor (F)VIII is the inactive precursor of FVIIIa, an essential component of the intrinsic tenase complex. Despite numerous structures of recombinant FVIII in solution, the structural basis of the procofactor-membrane interface remains poorly defined. Traditional liposome platforms require special grids and often suffer from heterogeneous particle distribution and overcrowding, precluding high-resolution single-particle analysis (SPA), while membrane mimetics, nanodiscs, are too planar posing significant biophysical challenges.
OBJECTIVES: To establish a reproducible methodology for structural determination of membrane-bound coagulation factors and resolve the procofactor FVIII-lipid interface.
METHODS: We used methylated branched lipids to compensate for membrane planarity and employed cryo-EM to solve the structure of FVIII bound to lipids.
RESULTS: We resolved the cryo-EM structure of procofactor FVIII on nanodiscs and liposomes lipid membranes at 3.46 - 3.56 Å, respectively. Structural analysis reveals a definitive tilted docking ...RESULTS: We resolved the cryo-EM structure of procofactor FVIII on nanodiscs and liposomes lipid membranes at 3.46 - 3.56 Å, respectively. Structural analysis reveals a definitive tilted docking orientation where both C domains mediate shallow interfacial insertion with the C2 domain acts as the primary anchor and the C1 domain serves as a secondary tether. This spatial arrangement structurally explains the high clinical severity of C2-interface mutations compared to more moderate C1 surface mutations.
CONCLUSION: Methylated branched lipids enable rapid, high-resolution characterization of membrane-associated clotting factors. This structure provides the first definitive template for the FVIII- ...CONCLUSION: Methylated branched lipids enable rapid, high-resolution characterization of membrane-associated clotting factors. This structure provides the first definitive template for the FVIII-lipid interface, serving as a benchmark for future studies on tenase complex assembly.
History
DepositionApr 8, 2026-
Header (metadata) releaseJun 10, 2026-
Map releaseJun 10, 2026-
UpdateJun 10, 2026-
Current statusJun 10, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76484.png

Downloads & links

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Map

FileDownload / File: emd_76484.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 416 pix.
= 386.048 Å		0.93 Å/pix.
x 416 pix.
= 386.048 Å		0.93 Å/pix.
x 416 pix.
= 386.048 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.928 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.144
Minimum - Maximum-0.2815679 - 0.5072909
Average (Standard dev.)-0.000046159996 (±0.009238535)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 386.04797 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_76484_msk_1.map
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Half map: #1

Fileemd_76484_half_map_1.map
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Half map: #2

Fileemd_76484_half_map_2.map
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Sample components

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Entire : Coagulation Factor VIII

EntireName: Coagulation Factor VIII
Components
  • Complex: Coagulation Factor VIII

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Supramolecule #1: Coagulation Factor VIII

SupramoleculeName: Coagulation Factor VIII / type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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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:
ConcentrationNameFormula
20.0 mM(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)
150.0 mMSodium ChlorideNaCl
5.0 mMCalcium ChlorideCaCl2
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 20 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 4185 / Average electron dose: 55.0 e/Å2 / Details: Cu R1.2/1.3
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 150000
Sample stageCooling holder cryogen: NITROGEN

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Image processing

Particle selectionNumber selected: 107362
CTF correctionSoftware - Name: cryoSPARC (ver. 5.0.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 5.0.1) / Number images used: 58291
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL

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