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- EMDB-43517: Cryo-EM structure of HMPV (MPV-2cREKR) -

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Basic information

Entry
Database: EMDB / ID: EMD-43517
TitleCryo-EM structure of HMPV (MPV-2cREKR)
Map data
Sample
  • Complex: Prefusion of HMPV (MPV-2cREKR) trimer complex
    • Protein or peptide: Prefusion of HMPV (MPV-2cREKR), N-fragment
    • Protein or peptide: Prefusion of HMPV (MPV-2cREKR), C-fragment
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsPrefusion / HMPV / Cryo-EM / VIRUS / VIRAL PROTEIN
Function / homologyPrecursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0 / symbiont entry into host cell / fusion of virus membrane with host plasma membrane / viral envelope / host cell plasma membrane / virion membrane / membrane / Fusion glycoprotein F0
Function and homology information
Biological speciesHuman metapneumovirus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.33 Å
AuthorsYu X / Langedijk JPM
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Efficacious human metapneumovirus vaccine based on AI-guided engineering of a closed prefusion trimer.
Authors: Mark J G Bakkers / Tina Ritschel / Machteld Tiemessen / Jacobus Dijkman / Angelo A Zuffianò / Xiaodi Yu / Daan van Overveld / Lam Le / Richard Voorzaat / Marlies M van Haaren / Martijn de ...Authors: Mark J G Bakkers / Tina Ritschel / Machteld Tiemessen / Jacobus Dijkman / Angelo A Zuffianò / Xiaodi Yu / Daan van Overveld / Lam Le / Richard Voorzaat / Marlies M van Haaren / Martijn de Man / Sem Tamara / Leslie van der Fits / Roland Zahn / Jarek Juraszek / Johannes P M Langedijk /
Abstract: The prefusion conformation of human metapneumovirus fusion protein (hMPV Pre-F) is critical for eliciting the most potent neutralizing antibodies and is the preferred immunogen for an efficacious ...The prefusion conformation of human metapneumovirus fusion protein (hMPV Pre-F) is critical for eliciting the most potent neutralizing antibodies and is the preferred immunogen for an efficacious vaccine against hMPV respiratory infections. Here we show that an additional cleavage event in the F protein allows closure and correct folding of the trimer. We therefore engineered the F protein to undergo double cleavage, which enabled screening for Pre-F stabilizing substitutions at the natively folded protomer interfaces. To identify these substitutions, we developed an AI convolutional classifier that successfully predicts complex polar interactions often overlooked by physics-based methods and visual inspection. The combination of additional processing, stabilization of interface regions and stabilization of the membrane-proximal stem, resulted in a Pre-F protein vaccine candidate without the need for a heterologous trimerization domain that exhibited high expression yields and thermostability. Cryo-EM analysis shows the complete ectodomain structure, including the stem, and a specific interaction of the newly identified cleaved C-terminus with the adjacent protomer. Importantly, the protein induces high and cross-neutralizing antibody responses resulting in near complete protection against hMPV challenge in cotton rats, making the highly stable, double-cleaved hMPV Pre-F trimer an attractive vaccine candidate.
History
DepositionJan 25, 2024-
Header (metadata) releaseJul 31, 2024-
Map releaseJul 31, 2024-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43517.png

Downloads & links

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Map

FileDownload / File: emd_43517.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.91 Å/pix.
x 320 pix.
= 291.2 Å		0.91 Å/pix.
x 320 pix.
= 291.2 Å		0.91 Å/pix.
x 320 pix.
= 291.2 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.91 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.083
Minimum - Maximum-1.1540033 - 1.6766881
Average (Standard dev.)0.000575105 (±0.036556065)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 291.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_43517_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_43517_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Prefusion of HMPV (MPV-2cREKR) trimer complex

EntireName: Prefusion of HMPV (MPV-2cREKR) trimer complex
Components
  • Complex: Prefusion of HMPV (MPV-2cREKR) trimer complex
    • Protein or peptide: Prefusion of HMPV (MPV-2cREKR), N-fragment
    • Protein or peptide: Prefusion of HMPV (MPV-2cREKR), C-fragment
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Prefusion of HMPV (MPV-2cREKR) trimer complex

SupramoleculeName: Prefusion of HMPV (MPV-2cREKR) trimer complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Human metapneumovirus

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Macromolecule #1: Prefusion of HMPV (MPV-2cREKR), N-fragment

MacromoleculeName: Prefusion of HMPV (MPV-2cREKR), N-fragment / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human metapneumovirus
Molecular weightTheoretical: 8.296239 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GLKESYLEES CSTITEGYLS VLRTGWYTNV FTLEVGDVEN LTCSDGPSLI KTELDLTKSA LRELKTVSAD QLARE

UniProtKB: Fusion glycoprotein F0

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Macromolecule #2: Prefusion of HMPV (MPV-2cREKR), C-fragment

MacromoleculeName: Prefusion of HMPV (MPV-2cREKR), C-fragment / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human metapneumovirus
Molecular weightTheoretical: 41.865828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: FVLGAIALGR ATAAAVTAGV AIAKTIRLES EVTAIKNALK TTNEAVSTLG NGVRVLATAV RELKDFVSKN LTRAINKNKC DIDDLKMAV SFSQFNRRFL NVVRQFSENA GITPAISLDL MTDAELARAI SNMPTSAGQI KLMLENRAMV RRKGFGILIG V YGSSVIYM ...String:
FVLGAIALGR ATAAAVTAGV AIAKTIRLES EVTAIKNALK TTNEAVSTLG NGVRVLATAV RELKDFVSKN LTRAINKNKC DIDDLKMAV SFSQFNRRFL NVVRQFSENA GITPAISLDL MTDAELARAI SNMPTSAGQI KLMLENRAMV RRKGFGILIG V YGSSVIYM VQLPIFGVID TPCWIVKAAP SCSEKKGNYA CLLREDQGWY CQNAGSTVYY PNEKDCETRG DHVFCDTAAG IN VAEQSKE CNINISTTNY PCKVSTGRNP ISMVALSPLG ALVACYKGVS CSIGSNRVGI IKQLNKGCSY ITNQDADTVT IDN TVYQLS KVEGEQHVIK GRPVSSSFDP IKFPPDQFNV ALDQVFENIE NSQAWVRKFD EILSSIEKG

UniProtKB: Fusion glycoprotein F0

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 3 / 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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.33 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 453003
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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