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- EMDB-48351: Pre-fusion HERV-K Envelope Protein Trimer Ectodomain in complex w... -

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Basic information

Entry
Database: EMDB / ID: EMD-48351
TitlePre-fusion HERV-K Envelope Protein Trimer Ectodomain in complex with Kenv-6 Fab
Map data
Sample
  • Complex: Pre-fusion HERV-K Envelope glycoprotein in complex with Kenv-6 Fabs
    • Complex: Pre-fusion Stabilized HERV-K Envelope Trimer
      • Protein or peptide: Surface protein
      • Protein or peptide: Transmembrane protein,Fibritin
    • Complex: Kenv-6 Antibody Fab
      • Protein or peptide: Kenv-6 Fab heavy chain
      • Protein or peptide: Kenv-6 Fab light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsHuman endogenous retrovirus K / glycoprotein / HERV-K / envelope / pre-fusion / Fab complex / VIRAL PROTEIN
Function / homology
Function and homology information


virion component / structural molecule activity / plasma membrane
Similarity search - Function
Retro-transcribing virus envelope glycoprotein / : / Retro-transcribing viruses envelope glycoprotein / Rec (regulator of expression encoded by corf) of HERV-K-113 / Fibritin C-terminal / Fibritin C-terminal region / Retroviral envelope protein / Retroviral envelope protein GP41-like
Similarity search - Domain/homology
Fibritin / Endogenous retrovirus group K member 25 Env polyprotein
Similarity search - Component
Biological speciesHomo sapiens (human) / Enterobacteria phage T4 (virus) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.24 Å
AuthorsShek J / Sun C / Hastie K / Saphire EO
Funding support United States, 2 items
OrganizationGrant numberCountry
Other private18030-01-000-408 United States
Other private13502-01-000-408 United States
CitationJournal: Sci Adv / Year: 2025
Title: Human endogenous retrovirus K (HERV-K) envelope structures in pre- and postfusion by cryo-EM.
Authors: Jeremy Shek / Chen Sun / Elise M Wilson / Fatemeh Moadab / Kathryn M Hastie / Roshan R Rajamanickam / Patrick J Penalosa / Stephanie S Harkins / Diptiben Parekh / Chitra Hariharan / Dawid S ...Authors: Jeremy Shek / Chen Sun / Elise M Wilson / Fatemeh Moadab / Kathryn M Hastie / Roshan R Rajamanickam / Patrick J Penalosa / Stephanie S Harkins / Diptiben Parekh / Chitra Hariharan / Dawid S Zyla / Cassandra Yu / Kelly C L Shaffer / Victoria I Lewis / Ruben Diaz Avalos / Tomas Mustelin / Erica Ollmann Saphire /
Abstract: Human endogenous retroviruses (HERVs) are remnants of ancient infections that comprise ~8% of the human genome. The HERV-K envelope glycoprotein (Env) is aberrantly expressed in cancers, autoimmune ...Human endogenous retroviruses (HERVs) are remnants of ancient infections that comprise ~8% of the human genome. The HERV-K envelope glycoprotein (Env) is aberrantly expressed in cancers, autoimmune disorders, and neurodegenerative diseases, and is targeted by patients' own antibodies. However, a lack of structural information has limited molecular and immunological studies of the roles of HERVs in disease. Here, we present cryo-electron microscopy structures of stabilized HERV-K Env in the prefusion conformation, revealing a distinct fold and architecture compared to HIV and simian immunodeficiency virus. We also generated and characterized a panel of monoclonal antibodies with subunit and conformational specificity, serving as valuable research tools. These antibodies enabled structure determination of the postfusion conformation of HERV-K Env, including its unique "tether" helix, and antibody-bound prefusion Env. Together, these results provide a structural framework that opens the door to mechanistic studies of HERV-K Env and tools for its evaluation as a potential therapeutic target.
History
DepositionDec 18, 2024-
Header (metadata) releaseJul 30, 2025-
Map releaseJul 30, 2025-
UpdateSep 3, 2025-
Current statusSep 3, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48351.png

Downloads & links

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Map

FileDownload / File: emd_48351.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.94 Å/pix.
x 448 pix.
= 422.401 Å		0.94 Å/pix.
x 448 pix.
= 422.401 Å		0.94 Å/pix.
x 448 pix.
= 422.401 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.94286 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.16
Minimum - Maximum-0.3505268 - 0.8903439
Average (Standard dev.)-0.000019405625 (±0.014573656)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 422.40128 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Sharpened Map

Fileemd_48351_additional_1.map
AnnotationSharpened Map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_48351_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_48351_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 : Pre-fusion HERV-K Envelope glycoprotein in complex with Kenv-6 Fabs

EntireName: Pre-fusion HERV-K Envelope glycoprotein in complex with Kenv-6 Fabs
Components
  • Complex: Pre-fusion HERV-K Envelope glycoprotein in complex with Kenv-6 Fabs
    • Complex: Pre-fusion Stabilized HERV-K Envelope Trimer
      • Protein or peptide: Surface protein
      • Protein or peptide: Transmembrane protein,Fibritin
    • Complex: Kenv-6 Antibody Fab
      • Protein or peptide: Kenv-6 Fab heavy chain
      • Protein or peptide: Kenv-6 Fab light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Pre-fusion HERV-K Envelope glycoprotein in complex with Kenv-6 Fabs

SupramoleculeName: Pre-fusion HERV-K Envelope glycoprotein in complex with Kenv-6 Fabs
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 500 KDa

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Supramolecule #2: Pre-fusion Stabilized HERV-K Envelope Trimer

SupramoleculeName: Pre-fusion Stabilized HERV-K Envelope Trimer / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Kenv-6 Antibody Fab

SupramoleculeName: Kenv-6 Antibody Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Details: Fab fragment generated by proteolytic cleave of Kenv-6 IgG antibody
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Surface protein

MacromoleculeName: Surface protein / type: protein_or_peptide / ID: 1
Details: Phoenix consensus sequence (Dewannieux, Marie, et al. 2006). Engineered V437C mutation
Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.193434 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: AAANYTYWAY VPFPPLIRAV TWMDNPIEVY VNDSVWVPGP IDDRCPAKPE EEGMMINISI GYRYPPICLG RAPGCLMPAV QNWLVEVPT VSPISRFTYH MVSGMSLRPR VNYLQDFSYQ RSLKFRPKGK PCPKEIPKES KNTEVLVWEE CVANSAVILQ N NEFGTIID ...String:
AAANYTYWAY VPFPPLIRAV TWMDNPIEVY VNDSVWVPGP IDDRCPAKPE EEGMMINISI GYRYPPICLG RAPGCLMPAV QNWLVEVPT VSPISRFTYH MVSGMSLRPR VNYLQDFSYQ RSLKFRPKGK PCPKEIPKES KNTEVLVWEE CVANSAVILQ N NEFGTIID WAPRGQFYHN CSGQTQSCPS AQVSPAVDSD LTESLDKHKH KKLQSFYPWE WGEKGISTPR PKIISPVSGP EH PELWRLT VASHHIRIWS GNQTLETRDR KPFYTVDLNS SLTVPLQSCV KPPYMLVVGN IVIKPDSQTI TCENCRLLTC IDS TFNWQH RILLVRAREG VWIPCSMDRP WEASPSIHIL TEVLKGVLNR RRR

UniProtKB: Endogenous retrovirus group K member 25 Env polyprotein

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Macromolecule #2: Transmembrane protein,Fibritin

MacromoleculeName: Transmembrane protein,Fibritin / type: protein_or_peptide / ID: 2
Details: Phoenix consensus sequence (Dewannieux, Marie, et al. 2006). Engineered V498C mutation. Fusion protein with enterokinase site, GGS linkers, and T4-fibritin foldon trimerization domain. C- ...Details: Phoenix consensus sequence (Dewannieux, Marie, et al. 2006). Engineered V498C mutation. Fusion protein with enterokinase site, GGS linkers, and T4-fibritin foldon trimerization domain. C-terminal HRV-3C protease site and twin-strep II tag.
Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Enterobacteria phage T4 (virus)
Molecular weightTheoretical: 27.4555 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: FIFTLIAVIM GLIAVTATAA VAGVALHSSV QSCNFVNDWQ KNSTRLWNSQ SSIDQKLANQ INDLRQTVIW MGDRLMSLEH RFQLQCDWN TSDFCITPQI YNESEHHWDM VRRHLQGRED NLTLDISKLK EQIFEASKAH LNLVPGTEAI AGVADGLANL N PVTWVKTD ...String:
FIFTLIAVIM GLIAVTATAA VAGVALHSSV QSCNFVNDWQ KNSTRLWNSQ SSIDQKLANQ INDLRQTVIW MGDRLMSLEH RFQLQCDWN TSDFCITPQI YNESEHHWDM VRRHLQGRED NLTLDISKLK EQIFEASKAH LNLVPGTEAI AGVADGLANL N PVTWVKTD DDDKAGGSGG SGGSGGGYIP EAPRDGQAYV RKDGEWVLLS TFLASGLEVL FQGPGAGWSH PQFEKGGGSG GG SGGGSWS HPQFEK

UniProtKB: Endogenous retrovirus group K member 25 Env polyprotein, Fibritin

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Macromolecule #3: Kenv-6 Fab heavy chain

MacromoleculeName: Kenv-6 Fab heavy chain / type: protein_or_peptide / ID: 3 / Details: Cleaved Fabs / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 13.437055 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
QIQLVQSGPE LKKPGETVKI SCKASGYTFT IYGMNWLKQA PGKGLKWMGW INTYTGEPTY ADDFKGRFAF SLETSASTAY LQVNNLKNE DTATYFCAKY YDGYYGWYFD VWGAGTTLTV

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Macromolecule #4: Kenv-6 Fab light chain

MacromoleculeName: Kenv-6 Fab light chain / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 11.671895 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
IVLTQSPASL AVTLGQRATI SCRGSESVDS YGNSFMHWYQ QKPGQPPKLL IYRASNLESG IPARFSGSGS RTDFTLTINP VEADDVATY YCQQSYEDPY TFGGGTKL

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Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration0.179 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
25.0 mMC4H11NO3Tris
150.0 mMNaClSodium Chloride

Details: Filtered and degassed
GridModel: C-flat-2/1 / Material: GRAPHENE OXIDE / Mesh: 300 / Support film - Material: GRAPHENE OXIDE / Support film - topology: CONTINUOUS
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 4 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 15947 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: OTHER / Imaging mode: OTHER / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.24 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 479625
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 10
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: OTHER
Output model

PDB-9mla:
Pre-fusion HERV-K Envelope Protein Trimer Ectodomain in complex with Kenv-6 Fab

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