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- EMDB-26704: Cryo-EM Structure of the Neutralizing Antibody MPV467 in Complex ... -

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Basic information

Entry
Database: EMDB / ID: EMD-26704
TitleCryo-EM Structure of the Neutralizing Antibody MPV467 in Complex with Prefusion Human Metapneumovirus F Glycoprotein
Map data
Sample
  • Complex: Trimeric prefusion hMPV F glycoprotein bound by three molecules of MPV467 Fab
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: MPV467 Fab Heavy chain
    • Protein or peptide: MPV467 Fab Light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homologyPrecursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0 / fusion of virus membrane with host plasma membrane / host cell plasma membrane / virion membrane / plasma membrane / Fusion glycoprotein F0
Function and homology information
Biological speciesHuman metapneumovirus / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsRush SA / McLellan JS
Funding support United States, 2 items
OrganizationGrant numberCountry
Welch FoundationF-0003-19620604 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RR160023 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus.
Authors: Avik Banerjee / Jiachen Huang / Scott A Rush / Jackelyn Murray / Aaron D Gingerich / Fredejah Royer / Ching-Lin Hsieh / Ralph A Tripp / Jason S McLellan / Jarrod J Mousa /
Abstract: Human metapneumovirus (hMPV) is a leading cause of morbidity and hospitalization among children worldwide, however, no vaccines or therapeutics are currently available for hMPV disease prevention and ...Human metapneumovirus (hMPV) is a leading cause of morbidity and hospitalization among children worldwide, however, no vaccines or therapeutics are currently available for hMPV disease prevention and treatment. The hMPV fusion (F) protein is the sole target of neutralizing antibodies. To map the immunodominant epitopes on the hMPV F protein, we isolated a panel of human monoclonal antibodies (mAbs), and the mAbs were assessed for binding avidity, neutralization potency, and epitope specificity. We found the majority of the mAbs target diverse epitopes on the hMPV F protein, and we discovered multiple mAb binding approaches for antigenic site III. The most potent mAb, MPV467, which had picomolar potency, was examined in prophylactic and therapeutic mouse challenge studies, and MPV467 limited virus replication in mouse lungs when administered 24 h before or 72 h after viral infection. We determined the structure of MPV467 in complex with the hMPV F protein using cryo-electron microscopy to a resolution of 3.3 Å, which revealed a complex novel prefusion-specific epitope overlapping antigenic sites II and V on a single protomer. Overall, our data reveal insights into the immunodominant antigenic epitopes on the hMPV F protein, identify a mAb therapy for hMPV F disease prevention and treatment, and provide the discovery of a prefusion-specific epitope on the hMPV F protein.
History
DepositionApr 21, 2022-
Header (metadata) releaseJun 8, 2022-
Map releaseJun 8, 2022-
UpdateJun 29, 2022-
Current statusJun 29, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26704.png

Downloads & links

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Map

FileDownload / File: emd_26704.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.269 Å
Density
Contour LevelBy AUTHOR: 0.14
Minimum - Maximum-0.31715444 - 0.94776106
Average (Standard dev.)0.000102876555 (±0.019885568)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 406.08002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_26704_msk_1.map
Projections & Slices
AxesZYX

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Additional map: #1

Fileemd_26704_additional_1.map
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Half map: #2

Fileemd_26704_half_map_1.map
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Half map: #1

Fileemd_26704_half_map_2.map
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Sample components

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Entire : Trimeric prefusion hMPV F glycoprotein bound by three molecules o...

EntireName: Trimeric prefusion hMPV F glycoprotein bound by three molecules of MPV467 Fab
Components
  • Complex: Trimeric prefusion hMPV F glycoprotein bound by three molecules of MPV467 Fab
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: MPV467 Fab Heavy chain
    • Protein or peptide: MPV467 Fab Light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Trimeric prefusion hMPV F glycoprotein bound by three molecules o...

SupramoleculeName: Trimeric prefusion hMPV F glycoprotein bound by three molecules of MPV467 Fab
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Human metapneumovirus / Strain: NL/1/00

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Macromolecule #1: Fusion glycoprotein F0

MacromoleculeName: Fusion glycoprotein F0 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human metapneumovirus
Molecular weightTheoretical: 60.48993 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSWKVVIIFS LLITPQHGLK ESYLEESCST ITEGYLSVLR TGWYTNVFTL EVGDVENLTC ADGPSLIKTE LDLTKSALRE LRTCSADQL AREEQIENPR RRRFVLGAIA CGVATAAAVT AGVAIAKCIR LESEVTAIKN CLKKTNECVS TLGCGVRVLA T AVRELKDF ...String:
MSWKVVIIFS LLITPQHGLK ESYLEESCST ITEGYLSVLR TGWYTNVFTL EVGDVENLTC ADGPSLIKTE LDLTKSALRE LRTCSADQL AREEQIENPR RRRFVLGAIA CGVATAAAVT AGVAIAKCIR LESEVTAIKN CLKKTNECVS TLGCGVRVLA T AVRELKDF VSKNLTRAIN KNKCDIPDLK MAVSFSQFNR RFLNVVRQFS DNAGITPAIS KDLMTDAELA RAISNMPTSA GQ IKLMLEN RCMVRRKGFG ILIGVYGSSV IYMVQLPIFG VIDTPCWIVK AAPSCSEKKG NYACLLREDQ GWYCQNAGST VYY PCEKDC ETRGDHVFCD TAAGINVAEQ SKECNINIST TNYPCKVSCG RHPISMVALS PLGALVACYK GVSCSIGSNR VGII KQLNK GCSYITNQDA DTVTIDNTVY QLSKVEGEQH VIKGRPVSSS FDPVKFPQDQ FNVALDQCFE SIENSQALVD QSNRI LSSA EKGNTGGGGS GYIPEAPRDG QAYVRKDGEW VLLSTFLGRS LEVLFQGPGH HHHHHHHSAW SHPQFEK

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Macromolecule #2: MPV467 Fab Heavy chain

MacromoleculeName: MPV467 Fab Heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.023779 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LVQSGGGVVR PGTSLRVSCA AFDFNFRDYG MHWVRQAPGK GLEWVAGIWY DGSNKDYADS VKGRFTISRD NSQNTLYLQM NSLRVEDTA VYYCARDPRT HREGALSHFD SWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT ...String:
LVQSGGGVVR PGTSLRVSCA AFDFNFRDYG MHWVRQAPGK GLEWVAGIWY DGSNKDYADS VKGRFTISRD NSQNTLYLQM NSLRVEDTA VYYCARDPRT HREGALSHFD SWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKR VEPKS

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Macromolecule #3: MPV467 Fab Light chain

MacromoleculeName: MPV467 Fab Light chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.621924 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ELTQDPAVSV ALGQTVRITC QGDSLRNYFA GWYQQKPGQA PLLVLYGENI RPSGIPDRFS GSSSGNTVSL TITGAQAEDE ADYYCNSRD NSGNHWVFGG GTRLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV E TTTPSKQS ...String:
ELTQDPAVSV ALGQTVRITC QGDSLRNYFA GWYQQKPGQA PLLVLYGENI RPSGIPDRFS GSSSGNTVSL TITGAQAEDE ADYYCNSRD NSGNHWVFGG GTRLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV E TTTPSKQS NNKYAASSYL SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TEC

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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: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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: 8
Component:
ConcentrationFormulaName
2.0 mMC4H11NO3Tris
200.0 mMNaClSodium chloridesodium chloride
0.02 %NaN3sodium azide
0.05 %amphipol
GridModel: C-flat-1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 150000
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2

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Image processing

Particle selectionNumber selected: 807472
CTF correctionSoftware - Name: cryoSPARC (ver. 3.2.0) / Software - details: cryoSPARC Live
Startup modelType of model: NONE / Details: ab initio
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 85671
FSC plot (resolution estimation)

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