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- EMDB-27024: Prefusion-stabilized hMPV fusion protein bound to ADI-61026 and M... -

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Basic information

Entry
Database: EMDB / ID: EMD-27024
TitlePrefusion-stabilized hMPV fusion protein bound to ADI-61026 and MPE8 Fabs
Map dataCompositeMap
Sample
  • Complex: hMPV fusion protein bound to ADI-61026 and MPE8 Fabs
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: MPE8 light chain
    • Protein or peptide: ADI-61026 heavy
    • Protein or peptide: ADI-61026 light
    • Protein or peptide: MPE8 heavy 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: 3.46 Å
AuthorsHsieh C-L / McLellan JS
Funding support United States, 1 items
OrganizationGrant numberCountry
Robert A. Welch FoundationF-0003-19620604 United States
CitationJournal: Immunity / Year: 2022
Title: Potently neutralizing and protective anti-human metapneumovirus antibodies target diverse sites on the fusion glycoprotein.
Authors: C Garrett Rappazzo / Ching-Lin Hsieh / Scott A Rush / Emma S Esterman / Teresa Delgado / James C Geoghegan / Anna Z Wec / Mrunal Sakharkar / Vicente Más / Jason S McLellan / Laura M Walker /
Abstract: Human metapneumovirus (hMPV) is a leading cause of acute lower respiratory tract infections in high-risk populations, yet there are no vaccines or anti-viral therapies approved for the prevention or ...Human metapneumovirus (hMPV) is a leading cause of acute lower respiratory tract infections in high-risk populations, yet there are no vaccines or anti-viral therapies approved for the prevention or treatment of hMPV-associated disease. Here, we used a high-throughput single-cell technology to interrogate memory B cell responses to the hMPV fusion (F) glycoprotein in young adult and elderly donors. Across all donors, the neutralizing antibody response was primarily directed to epitopes expressed on both pre- and post-fusion F conformations. However, we identified rare, highly potent broadly neutralizing antibodies that recognize pre-fusion-specific epitopes and structurally characterized an antibody that targets a site of vulnerability at the pre-fusion F trimer apex. Additionally, monotherapy with neutralizing antibodies targeting three distinct antigenic sites provided robust protection against lower respiratory tract infection in a small animal model. This study provides promising monoclonal antibody candidates for passive immunoprophylaxis and informs the rational design of hMPV vaccine immunogens.
History
DepositionMay 18, 2022-
Header (metadata) releaseAug 10, 2022-
Map releaseAug 10, 2022-
UpdateFeb 22, 2023-
Current statusFeb 22, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27024.png

Downloads & links

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Map

FileDownload / File: emd_27024.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCompositeMap
Voxel sizeX=Y=Z: 1.36688 Å
Density
Contour LevelBy AUTHOR: 6.2
Minimum - Maximum-3.7248635 - 74.06204
Average (Standard dev.)0.0021115714 (±1.0193162)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 349.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : hMPV fusion protein bound to ADI-61026 and MPE8 Fabs

EntireName: hMPV fusion protein bound to ADI-61026 and MPE8 Fabs
Components
  • Complex: hMPV fusion protein bound to ADI-61026 and MPE8 Fabs
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: MPE8 light chain
    • Protein or peptide: ADI-61026 heavy
    • Protein or peptide: ADI-61026 light
    • Protein or peptide: MPE8 heavy chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: hMPV fusion protein bound to ADI-61026 and MPE8 Fabs

SupramoleculeName: hMPV fusion protein bound to ADI-61026 and MPE8 Fabs / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Human metapneumovirus

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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: 60.453852 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSWKVVIIFS LLITPQHGLK ESYLEESCST ITEGYLSVLR TGWYTNVFTL EVGDVENLTC ADGPSLIKTE LDLTKSALRE LRTVSADQL AREEQIENPR RRRFVLGAIA CGVATAAAVT AGVAIAKCIR LESEVTAIKN CLKKTNECVS TLGCGVRVLA T AVRELKDF ...String:
MSWKVVIIFS LLITPQHGLK ESYLEESCST ITEGYLSVLR TGWYTNVFTL EVGDVENLTC ADGPSLIKTE LDLTKSALRE LRTVSADQL AREEQIENPR RRRFVLGAIA CGVATAAAVT AGVAIAKCIR LESEVTAIKN CLKKTNECVS TLGCGVRVLA T AVRELKDF VSKNLTRAIN KNKCDIPDLK MAVSFSQFNR RFLNVVRQFS DNAGITPAIS KDLMTDAELA RAISNMPTSA GQ IKLMLEN RAMVRRKGFG 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: MPE8 light chain

MacromoleculeName: MPE8 light chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.772092 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSVVTQPPSV SGAPGQRVTI SCTGSSSNIG AGYDVHWYQQ LPGTAPKLLI YDNNNRPSGV PDRFSASKSG TSASLAITGL QAEDEADYY CQSYDRSLSG VFGTGTKVTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKADSSPV K AGVETTTP ...String:
QSVVTQPPSV SGAPGQRVTI SCTGSSSNIG AGYDVHWYQQ LPGTAPKLLI YDNNNRPSGV PDRFSASKSG TSASLAITGL QAEDEADYY CQSYDRSLSG VFGTGTKVTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKADSSPV K AGVETTTP SKQSNNKYAA SSYLSLTPEQ WKSHKSYSCQ VTHEGSTVEK TVAPTECS

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Macromolecule #3: ADI-61026 heavy

MacromoleculeName: ADI-61026 heavy / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.699928 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQSGPA LVKSTQTLTL TCTFSGFALT TSGMCVSWVR QPPGKALEWL ARIDWEDNTY YSTSLKTRVT ISKDPSKNQV VLTMTNMDP VDTATYYCAR SYITDWKKDW FFDLWGRGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ...String:
QVQLVQSGPA LVKSTQTLTL TCTFSGFALT TSGMCVSWVR QPPGKALEWL ARIDWEDNTY YSTSLKTRVT ISKDPSKNQV VLTMTNMDP VDTATYYCAR SYITDWKKDW FFDLWGRGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCD

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Macromolecule #4: ADI-61026 light

MacromoleculeName: ADI-61026 light / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.912414 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SYELIQLPSV SVSPGQTARI PCSGDGLPKK YAHWYQQKAG QAPILLMYKD SERPSGIPER FSAFSSGTTV TMTISGVQEE DEADYYCQS GDSTDTSVIF GGGTKVTVLG QPKAAPSVTL FPPSSEELQA NKATLVCLIS DFYPGAVTVA WKADSSPVKA G VETTTPSK ...String:
SYELIQLPSV SVSPGQTARI PCSGDGLPKK YAHWYQQKAG QAPILLMYKD SERPSGIPER FSAFSSGTTV TMTISGVQEE DEADYYCQS GDSTDTSVIF GGGTKVTVLG QPKAAPSVTL FPPSSEELQA NKATLVCLIS DFYPGAVTVA WKADSSPVKA G VETTTPSK QSNNKYAASS YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS

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Macromolecule #5: MPE8 heavy chain

MacromoleculeName: MPE8 heavy chain / type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.433516 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG LVKPGGSLRL SCAASGFTFS SYSMNWVRQA PGKGLEWVSS ISASSSYSDY ADSAKGRFTI SRDNAKTSLF LQMNSLRAE DTAIYFCARA RATGYSSITP YFDIWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ...String:
EVQLVESGGG LVKPGGSLRL SCAASGFTFS SYSMNWVRQA PGKGLEWVSS ISASSSYSDY ADSAKGRFTI SRDNAKTSLF LQMNSLRAE DTAIYFCARA RATGYSSITP YFDIWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCD KTHTCPPCPA PE LLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDW LNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKT TPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 3 / 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

Concentration0.36 mg/mL
BufferpH: 8
Details: 2 mM Tris pH 8.0, 200 mM NaCl, 0.02% NaN3, 0.075% amphipol
GridModel: C-flat-1.2/1.3 / Material: COPPER / Mesh: 400 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 K
Details0.36 mg/mL hMPV F (2 mM Tris pH 8.0, 200 mM NaCl, 0.02% NaN3, 0.075% amphipol) and 2-folds molar excess MPE8 and 1.5- folds molar excess ADI-61026

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 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: 1.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 70.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 113336

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