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- EMDB-70774: CryoEM map of 4F11 and MxR Fabs bound to HMPV DS-CavEs2 preF monomer -

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Basic information

Entry
Database: EMDB / ID: EMD-70774
TitleCryoEM map of 4F11 and MxR Fabs bound to HMPV DS-CavEs2 preF monomer
Map data
Sample
  • Complex: 4F11 and MxR Fabs bound to HMPV DS-CavEs2 preF monomer
KeywordsIMMUNE SYSTEM / HMPV / PREFUSION F / ANTIBODY / SITE 0 / GLYCAN DEPENDENT
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.03 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_70774.png

Downloads & links

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Map

FileDownload / File: emd_70774.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.12 Å/pix.
x 256 pix.
= 287.232 Å		1.12 Å/pix.
x 256 pix.
= 287.232 Å		1.12 Å/pix.
x 256 pix.
= 287.232 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: 0.596
Minimum - Maximum-3.1518574 - 5.3045063
Average (Standard dev.)0.0015166586 (±0.10029548)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 287.232 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_70774_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_70774_half_map_2.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : 4F11 and MxR Fabs bound to HMPV DS-CavEs2 preF monomer

EntireName: 4F11 and MxR Fabs bound to HMPV DS-CavEs2 preF monomer
Components
  • Complex: 4F11 and MxR Fabs bound to HMPV DS-CavEs2 preF monomer

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Supramolecule #1: 4F11 and MxR Fabs bound to HMPV DS-CavEs2 preF monomer

SupramoleculeName: 4F11 and MxR Fabs bound to HMPV DS-CavEs2 preF monomer
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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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

Concentration3.5 mg/mL
BufferpH: 7.2
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300
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: 2.2 µm / Nominal defocus min: 1.6 µm

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Image processing

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

7sej

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.03 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 101166
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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