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- EMDB-70773: CryoEM structure of 4F11 Fab bound to stabilized MPV-2c HMPV preF -

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Basic information

Entry
Database: EMDB / ID: EMD-70773
TitleCryoEM structure of 4F11 Fab bound to stabilized MPV-2c HMPV preF
Map data
Sample
  • Complex: 4F11 Fab bound to MPV-2c
    • Complex: MPV-2c
      • Protein or peptide: Fusion glycoprotein F0
    • Complex: 4F11 Fab
      • Protein or peptide: 4F11 Heavy Chain
      • Protein or peptide: 4F11 Light Chain
  • Protein or peptide: Fusion glycoprotein F0
  • Protein or peptide: Fusion glycoprotein F0
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsIMMUNE SYSTEM / HMPV / prefusion F / ANTIBODY / site 0 / glycan dependent
Function / homology
Function and homology information


fusion of virus membrane with host plasma membrane / viral envelope / symbiont entry into host cell / host cell plasma membrane / virion membrane / membrane
Similarity search - Function
Precursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0
Similarity search - Domain/homology
Fusion glycoprotein F0 / Fusion glycoprotein F0
Similarity search - Component
Biological specieshuman metapneumovirus / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.13 Å
AuthorsMcGovern MR / Pancera M
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI171186 United States
CitationJournal: bioRxiv / Year: 2025
Title: DEVELOPMENT OF A POTENT MONOCLONAL ANTIBODY FOR TREATMENT OF HUMAN METAPNEUMOVIRUS INFECTIONS.
Authors: Evelyn D Harris / Morgan McGovern / Sara Pernikoff / Ren Ikeda / Lea Kipnis / William Hannon / Elizabeth B Sobolik / Matthew Gray / Alexander L Greninger / Sijia He / Chen-Ni Chin / Tong- ...Authors: Evelyn D Harris / Morgan McGovern / Sara Pernikoff / Ren Ikeda / Lea Kipnis / William Hannon / Elizabeth B Sobolik / Matthew Gray / Alexander L Greninger / Sijia He / Chen-Ni Chin / Tong-Ming Fu / Marie Pancera / Jim Boonyaratanakornkit /
Abstract: Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a ...Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a promising approach for both treatment and prevention. Here, we describe the discovery and characterization of 4F11, a highly potent and broadly neutralizing mAb with demonstrated in vitro and in vivo efficacy against HMPV. Using cryo-electron microscopy, we defined a unique mechanism of binding HMPV employed by 4F11, which distinguishes it from previously characterized RSV and HMPV mAbs. 4F11 targets an epitope located at the apex of the prefusion F protein (site Ø) with a 1:1 stoichiometry, distinct from the 3:1 stoichiometry observed with other HMPV site Ø antibodies. Unlike other site Ø antibodies, which penetrate the glycan shield between Asn57 and Asn172, 4F11 binds vertically and directly interacts with the Asn172 glycan, representing a unique glycan-dependent mode of recognition. In vitro, 4F11 displayed high potency and broad neutralization across diverse HMPV strains. It also showed a low propensity for resistance development, with only a single escape mutation (K179E) identified, a mutation not found in any published HMPV sequence to date. Viruses rescued with the K179E escape mutation had significantly decreased fitness in vitro compared to wild-type virus. In a hamster challenge model, 4F11 significantly reduced viral loads in both the lungs and nasal turbinates. These findings highlight 4F11 as a promising candidate for therapeutic development, particularly for immunocompromised individuals and other high-risk groups.
History
DepositionMay 21, 2025-
Header (metadata) releaseJul 30, 2025-
Map releaseJul 30, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70773.png

Downloads & links

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Map

FileDownload / File: emd_70773.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.12 Å/pix.
x 360 pix.
= 403.92 Å		1.12 Å/pix.
x 360 pix.
= 403.92 Å		1.12 Å/pix.
x 360 pix.
= 403.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.122 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.812
Minimum - Maximum-2.3612936 - 4.0242877
Average (Standard dev.)-0.00005531221 (±0.07531574)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 403.91998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_70773_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_70773_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 : 4F11 Fab bound to MPV-2c

EntireName: 4F11 Fab bound to MPV-2c
Components
  • Complex: 4F11 Fab bound to MPV-2c
    • Complex: MPV-2c
      • Protein or peptide: Fusion glycoprotein F0
    • Complex: 4F11 Fab
      • Protein or peptide: 4F11 Heavy Chain
      • Protein or peptide: 4F11 Light Chain
  • Protein or peptide: Fusion glycoprotein F0
  • Protein or peptide: Fusion glycoprotein F0
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: 4F11 Fab bound to MPV-2c

SupramoleculeName: 4F11 Fab bound to MPV-2c / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #4-#5

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Supramolecule #2: MPV-2c

SupramoleculeName: MPV-2c / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: human metapneumovirus

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Supramolecule #3: 4F11 Fab

SupramoleculeName: 4F11 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Fusion glycoprotein F0

MacromoleculeName: Fusion glycoprotein F0 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: human metapneumovirus
Molecular weightTheoretical: 47.56616 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KESYLEESCS TITEGYLSVL RTGWYTNVFT LEVGDVENLT CSDGPSLIKT ELDLTKSALR ELKTVSADQL RFVLGAIALG RATAAAVTA GVAIAKTIRL ESEVTAIKNA LKTTNEAVST LGNGVRVLAT AVRELKDFVS KNLTRAINKN KCDIDDLKMA V SFSQFNRR ...String:
KESYLEESCS TITEGYLSVL RTGWYTNVFT LEVGDVENLT CSDGPSLIKT ELDLTKSALR ELKTVSADQL RFVLGAIALG RATAAAVTA GVAIAKTIRL ESEVTAIKNA LKTTNEAVST LGNGVRVLAT AVRELKDFVS KNLTRAINKN KCDIDDLKMA V SFSQFNRR FLNVVRQFSE NAGITPAISL DLMTDAELAR AISNMPTSAG QIKLMLENRA MVRRKGFGIL IGVYGSSVIY MV QLPIFGV IDTPCWIVKA APSCSEKKGN YACLLREDQG WYCQNAGSTV YYPNEKDCET RGDHVFCDTA AGINVAEQSK ECN INISTT NYPCKVSTGR NPISMVALSP LGALVACYKG VSCSIGSNRV GIIKQLNKGC SYITNQDADT VTIDNTVYQL SKVE GEQHV IKGRPVSSSF DPIKFPPDQF NVALDQVFEN IN

UniProtKB: Fusion glycoprotein F0

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Macromolecule #2: Fusion glycoprotein F0

MacromoleculeName: Fusion glycoprotein F0 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: human metapneumovirus
Molecular weightTheoretical: 47.67932 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LKESYLEESC STITEGYLSV LRTGWYTNVF TLEVGDVENL TCSDGPSLIK TELDLTKSAL RELKTVSADQ LRFVLGAIAL GRATAAAVT AGVAIAKTIR LESEVTAIKN ALKTTNEAVS TLGNGVRVLA TAVRELKDFV SKNLTRAINK NKCDIDDLKM A VSFSQFNR ...String:
LKESYLEESC STITEGYLSV LRTGWYTNVF TLEVGDVENL TCSDGPSLIK TELDLTKSAL RELKTVSADQ LRFVLGAIAL GRATAAAVT AGVAIAKTIR LESEVTAIKN ALKTTNEAVS TLGNGVRVLA TAVRELKDFV SKNLTRAINK NKCDIDDLKM A VSFSQFNR RFLNVVRQFS ENAGITPAIS LDLMTDAELA RAISNMPTSA GQIKLMLENR AMVRRKGFGI LIGVYGSSVI YM VQLPIFG VIDTPCWIVK AAPSCSEKKG NYACLLREDQ GWYCQNAGST VYYPNEKDCE TRGDHVFCDT AAGINVAEQS KEC NINIST TNYPCKVSTG RNPISMVALS PLGALVACYK GVSCSIGSNR VGIIKQLNKG CSYITNQDAD TVTIDNTVYQ LSKV EGEQH VIKGRPVSSS FDPIKFPPDQ FNVALDQVFE NIN

UniProtKB: Fusion glycoprotein F0

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Macromolecule #3: Fusion glycoprotein F0

MacromoleculeName: Fusion glycoprotein F0 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: human metapneumovirus
Molecular weightTheoretical: 47.836512 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LKESYLEESC STITEGYLSV LRTGWYTNVF TLEVGDVENL TCSDGPSLIK TELDLTKSAL RELKTVSADQ LRRFVLGAIA LGRATAAAV TAGVAIAKTI RLESEVTAIK NALKTTNEAV STLGNGVRVL ATAVRELKDF VSKNLTRAIN KNKCDIDDLK M AVSFSQFN ...String:
LKESYLEESC STITEGYLSV LRTGWYTNVF TLEVGDVENL TCSDGPSLIK TELDLTKSAL RELKTVSADQ LRRFVLGAIA LGRATAAAV TAGVAIAKTI RLESEVTAIK NALKTTNEAV STLGNGVRVL ATAVRELKDF VSKNLTRAIN KNKCDIDDLK M AVSFSQFN RRFLNVVRQF SENAGITPAI SLDLMTDAEL ARAISNMPTS AGQIKLMLEN RAMVRRKGFG ILIGVYGSSV IY MVQLPIF GVIDTPCWIV KAAPSCSEKK GNYACLLRED QGWYCQNAGS TVYYPNEKDC ETRGDHVFCD TAAGINVAEQ SKE CNINIS TTNYPCKVST GRNPISMVAL SPLGALVACY KGVSCSIGSN RVGIIKQLNK GCSYITNQDA DTVTIDNTVY QLSK VEGEQ HVIKGRPVSS SFDPIKFPPD QFNVALDQVF ENIN

UniProtKB: Fusion glycoprotein F0

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Macromolecule #4: 4F11 Heavy Chain

MacromoleculeName: 4F11 Heavy Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.72836 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQLVQSGAE VKKPGDSLKI SCKGSGYKFA TYWIGWVRQM PGKGLEWMGV IYPDDSDTRY SPSFQGQVSI SVDKSITTAY LQWSSLKAS DTAIYYCARC YDFWSGYQFG MDVWGQGTTV TVSS

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Macromolecule #5: 4F11 Light Chain

MacromoleculeName: 4F11 Light Chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.38795 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DIVMTQSPLS LPVTPGETAS ISCRSSQSLR HDNGYNYLDW YLQKPGQSPQ LLIYLGSKRA SGVPDRFSGS GSGTDFTLKI SRVEAEDVG VYYCMQTLQT LMFTFGGGTK VEIK

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Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / 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

Concentration2 mg/mL
BufferpH: 7.4
GridModel: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8vt2

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.13 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 276088
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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