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- PDB-9kay: Bioengineered protein nanocarrier facilitating siRNA escape from ... -

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Basic information

Entry
Database: PDB / ID: 9kay
TitleBioengineered protein nanocarrier facilitating siRNA escape from lysosomes for targeted RNAi therapy in glioblastoma
ComponentsFerritin heavy chain, N-terminally processed
KeywordsMETAL TRANSPORT / Bioengineered ferritin / Lysosomal escape / siRNA delivery / Glioblastoma targeted therapy / EGFR and TERT
Function / homology
Function and homology information


iron ion sequestering activity / ferritin complex / Scavenging by Class A Receptors / negative regulation of ferroptosis / Golgi Associated Vesicle Biogenesis / ferroxidase / autolysosome / ferroxidase activity / negative regulation of fibroblast proliferation / ferric iron binding ...iron ion sequestering activity / ferritin complex / Scavenging by Class A Receptors / negative regulation of ferroptosis / Golgi Associated Vesicle Biogenesis / ferroxidase / autolysosome / ferroxidase activity / negative regulation of fibroblast proliferation / ferric iron binding / autophagosome / iron ion transport / Iron uptake and transport / ferrous iron binding / tertiary granule lumen / ficolin-1-rich granule lumen / intracellular iron ion homeostasis / immune response / iron ion binding / negative regulation of cell population proliferation / Neutrophil degranulation / extracellular exosome / extracellular region / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Ferritin iron-binding regions signature 1. / Ferritin iron-binding regions signature 2. / Ferritin, conserved site / Ferritin / Ferritin-like diiron domain / Ferritin-like diiron domain profile. / Ferritin/DPS protein domain / Ferritin-like domain / Ferritin-like / Ferritin-like superfamily
Similarity search - Domain/homology
Ferritin heavy chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 1.73 Å
AuthorsChen, X. / Fan, K.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2021YFA1201102 China
CitationJournal: Sci Adv / Year: 2025
Title: Bioengineered protein nanocarrier facilitating siRNA escape from lysosomes for targeted RNAi therapy in glioblastoma.
Authors: Yiliang Jin / Baoli Zhang / Jianru Li / Zhenxi Guo / Chen Zhang / Xuehui Chen / Long Ma / Zhuoran Wang / Haiyin Yang / Yong Li / Yuhua Weng / Yuanyu Huang / Xiyun Yan / Kelong Fan /
Abstract: RNA interference (RNAi) represents a promising gene-specific therapy against tumors. However, its clinical translation is impeded by poor performance of lysosomal escape and tumor targeting. This ...RNA interference (RNAi) represents a promising gene-specific therapy against tumors. However, its clinical translation is impeded by poor performance of lysosomal escape and tumor targeting. This challenge is especially prominent in glioblastoma (GBM) therapy, necessitating the penetration of the blood-brain barrier (BBB). Leveraging the intrinsic tumor-targeting and BBB traversing capability of human H-ferritin, we designed a series of ferritin variants with positively charged cavity and truncated carboxyl terminus, termed tHFn(+). These nanocarriers respond to weak acid and disassemble in endosomal compartments, exposing the internal positive charges to facilitate the lysosomal escape of loaded small interfering RNA (siRNA). Functioning as universal siRNA nanocarriers, tHFn(+) significantly enhanced the uptake of different siRNAs and suppressed gene expressions associated with GBM progression. Furthermore, tHFn(+) traversed the BBB and targeted glioma in vivo by binding to its receptors (e.g., transferrin receptor 1). tHFn(+)-delivered siRNAs exhibited exceptional therapeutic effects against glioma in vivo, advancing RNAi therapeutics beyond GBM for the treatment of various diseases.
History
DepositionOct 30, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
Aa: Ferritin heavy chain, N-terminally processed
Ab: Ferritin heavy chain, N-terminally processed
Ac: Ferritin heavy chain, N-terminally processed
Ad: Ferritin heavy chain, N-terminally processed
Ae: Ferritin heavy chain, N-terminally processed
Af: Ferritin heavy chain, N-terminally processed
Ag: Ferritin heavy chain, N-terminally processed
Ah: Ferritin heavy chain, N-terminally processed
Ai: Ferritin heavy chain, N-terminally processed
Aj: Ferritin heavy chain, N-terminally processed
Ak: Ferritin heavy chain, N-terminally processed
Al: Ferritin heavy chain, N-terminally processed
Am: Ferritin heavy chain, N-terminally processed
An: Ferritin heavy chain, N-terminally processed
Ao: Ferritin heavy chain, N-terminally processed
Ap: Ferritin heavy chain, N-terminally processed
Aq: Ferritin heavy chain, N-terminally processed
Ar: Ferritin heavy chain, N-terminally processed
As: Ferritin heavy chain, N-terminally processed
At: Ferritin heavy chain, N-terminally processed
Au: Ferritin heavy chain, N-terminally processed
Av: Ferritin heavy chain, N-terminally processed
Aw: Ferritin heavy chain, N-terminally processed
Ax: Ferritin heavy chain, N-terminally processed


Theoretical massNumber of molelcules
Total (without water)448,15624
Polymers448,15624
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 ...
Ferritin heavy chain, N-terminally processed


Mass: 18673.164 Da / Num. of mol.: 24 / Mutation: E61K,E64R,E140K,E147K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FTH1, FTH, FTHL6, OK/SW-cl.84, PIG15 / Production host: Escherichia coli (E. coli) / References: UniProt: P02794
Has protein modificationN

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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: human ferritin heavy chain mutant / Type: ORGANELLE OR CELLULAR COMPONENT / Details: 1-159, E61K/E64R/E140K/E147K / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 18.6 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (Human) (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8 / Details: 20 mM Tris, pH8.0, 50 mM NaCl
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 700 nm / Nominal defocus min: 300 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.18.2_3874: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1725802
3D reconstructionResolution: 1.73 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 966873 / Symmetry type: POINT

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