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- PDB-9jbv: Structure of Engineered Coagulation Factor VIII with Enhanced Sec... -

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Basic information

Entry
Database: PDB / ID: 9jbv
TitleStructure of Engineered Coagulation Factor VIII with Enhanced Secretion and Coagulation Potential
ComponentsCoagulation factor VIII
KeywordsBLOOD CLOTTING / hemophilia
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 / COPII-coated ER to Golgi transport vesicle / Defective factor IX causes thrombophilia ...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 / COPII-coated ER to Golgi transport vesicle / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / COPII-mediated vesicle transport / Defective F8 cleavage by thrombin / : / : / 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 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, N-terminal / Multicopper oxidase / Cupredoxin / Galactose-binding-like domain superfamily
Similarity search - Domain/homology
Coagulation factor VIII
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.17 Å
AuthorsKio, H. / Osamu, N. / Tsukasa, O.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED) Japan
CitationJournal: Blood / Year: 2026
Title: Engineered coagulation factor VIII with enhanced secretion and coagulation potential for hemophilia A gene therapy.
Authors: Yuji Kashiwakura / Yuto Nakajima / Kio Horinaka / Tiago J S Lopes / Yuma Furuta / Yuki Yamaguchi / Nemekhbayar Baatartsogt / Morisada Hayakawa / Yuko Katakai / Susumu Uchiyama / Osamu Nureki ...Authors: Yuji Kashiwakura / Yuto Nakajima / Kio Horinaka / Tiago J S Lopes / Yuma Furuta / Yuki Yamaguchi / Nemekhbayar Baatartsogt / Morisada Hayakawa / Yuko Katakai / Susumu Uchiyama / Osamu Nureki / Keiji Nogami / Tsukasa Ohmori /
Abstract: The major challenges of gene therapy for hemophilia A using adeno-associated virus (AAV) vectors are reducing vector doses and the long-term maintenance of stable factor VIII (FVIII). In this study, ...The major challenges of gene therapy for hemophilia A using adeno-associated virus (AAV) vectors are reducing vector doses and the long-term maintenance of stable factor VIII (FVIII). In this study, we developed engineered human B-domain-deleted FVIIIs (FVIIISQ) with enhanced secretion and coagulation potential. Intracellular accumulation was markedly reduced in some engineered FVIIISQ, resulting in reduced unfolded protein responses. The administration of AAV vectors carrying engineered FVIIISQ to hemophilia A mice resulted in ∼8-fold higher FVIII activity and 4-fold higher FVIII antigen levels compared with wild-type FVIIISQ administration. The specific FVIII activity of the engineered FVIIISQ was 3.6 times higher than that of the wild-type FVIIISQ, and its binding to activated coagulation factor IX was significantly enhanced, which is supported by the structural analysis. In macaques, the administration of AAV5 vector carrying the engineered FVIIISQ without CpG sequences resulted in a supraphysiological increase in plasma FVIII activity at a dose one-thirtieth that of valoctocogene roxaparvovec (2 × 1012 vector genome per kg). The engineered FVIIISQ may thus provide stable, long-term therapeutic efficacy in AAV-mediated hemophilia A gene therapy even at low doses.
History
DepositionAug 27, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 10, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Coagulation factor VIII


Theoretical massNumber of molelcules
Total (without water)167,4521
Polymers167,4521
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 167452.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F8, F8C / Production host: Homo sapiens (human) / References: UniProt: P00451
Has protein modificationY

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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: Engineered Coagulation Factor VIII with Enhanced Secretion and Coagulation Potential
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.3
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 218890 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00310575
ELECTRON MICROSCOPYf_angle_d0.46514336
ELECTRON MICROSCOPYf_dihedral_angle_d4.0451388
ELECTRON MICROSCOPYf_chiral_restr0.0431534
ELECTRON MICROSCOPYf_plane_restr0.0031829

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