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- EMDB-23566: The SARS-CoV-2 spike protein receptor binding domain bound to neu... -

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Basic information

Entry
Database: EMDB / ID: EMD-23566
TitleThe SARS-CoV-2 spike protein receptor binding domain bound to neutralizing nanobodies WNb 2 and WNb 10
Map dataPostprocessed map. B -60
Sample
  • Complex: Focused refinement of the SARS-CoV-2 spike protein receptor binding domain bound to neutralizing nanobodies WNb 2 and WNb 10
    • Complex: SARS-CoV-2 spike protein receptor binding domain
      • Protein or peptide: Spike glycoprotein
    • Complex: neutralizing nanobodies WNb 2 and WNb 10
      • Protein or peptide: WNb 2
      • Protein or peptide: WNb 10
KeywordsSARS-CoV-2 / nanobody cocktail / coronavirus spike / neutralizing nanobody / VIRAL PROTEIN
Function / homology
Function and homology information


Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / suppression by virus of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell ...Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / suppression by virus of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / membrane fusion / receptor-mediated endocytosis of virus by host cell / Attachment and Entry / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / receptor ligand activity / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell plasma membrane / virion membrane / identical protein binding / membrane / plasma membrane
Similarity search - Function
Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus ...Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S2, coronavirus, heptad repeat 1 / Spike glycoprotein S2, coronavirus, heptad repeat 2 / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 2 (HR2) region profile. / Spike glycoprotein S2 superfamily, coronavirus / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2
Similarity search - Domain/homology
Biological speciesSevere acute respiratory syndrome coronavirus 2 / Vicugna pacos (alpaca)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.44 Å
AuthorsPymm P / Glukhova A
Funding support Australia, 2 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)GNT2002073 Australia
Wellcome Trust208693/Z/17/Z Australia
CitationJournal: Proc Natl Acad Sci U S A / Year: 2021
Title: Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice.
Authors: Phillip Pymm / Amy Adair / Li-Jin Chan / James P Cooney / Francesca L Mordant / Cody C Allison / Ester Lopez / Ebene R Haycroft / Matthew T O'Neill / Li Lynn Tan / Melanie H Dietrich / ...Authors: Phillip Pymm / Amy Adair / Li-Jin Chan / James P Cooney / Francesca L Mordant / Cody C Allison / Ester Lopez / Ebene R Haycroft / Matthew T O'Neill / Li Lynn Tan / Melanie H Dietrich / Damien Drew / Marcel Doerflinger / Michael A Dengler / Nichollas E Scott / Adam K Wheatley / Nicholas A Gherardin / Hariprasad Venugopal / Deborah Cromer / Miles P Davenport / Raelene Pickering / Dale I Godfrey / Damian F J Purcell / Stephen J Kent / Amy W Chung / Kanta Subbarao / Marc Pellegrini / Alisa Glukhova / Wai-Hong Tham /
Abstract: Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas ...Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites and showed two neutralizing nanobodies from different epitope classes bound simultaneously to the spike trimer. Nanobody-Fc fusions of the four most potent nanobodies blocked ACE2 engagement with RBD variants present in human populations and potently neutralized both wild-type SARS-CoV-2 and the N501Y D614G variant at concentrations as low as 0.1 nM. Prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 10-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2.
History
DepositionMar 3, 2021-
Header (metadata) releaseMay 5, 2021-
Map releaseMay 5, 2021-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with fitted model
  • Atomic models: PDB-7lx5
  • Surface level: 0.012
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-7lx5
  • Surface level: 0.012
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23566.png

Downloads & links

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Map

FileDownload / File: emd_23566.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPostprocessed map. B -60
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 180 pix.
= 154.8 Å		0.86 Å/pix.
x 180 pix.
= 154.8 Å		0.86 Å/pix.
x 180 pix.
= 154.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.008 / Movie #1: 0.012
Minimum - Maximum-0.071658805 - 0.09544541
Average (Standard dev.)0.000049786726 (±0.0020601805)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 154.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.860.860.86
M x/y/z180180180
origin x/y/z0.0000.0000.000
length x/y/z154.800154.800154.800
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS180180180
D min/max/mean-0.0720.0950.000

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Supplemental data

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Mask #1

Fileemd_23566_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Map from Refine 3D

Fileemd_23566_additional_1.map
AnnotationMap from Refine 3D
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1

Fileemd_23566_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_23566_half_map_2.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram (log scale)

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Sample components

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Entire : Focused refinement of the SARS-CoV-2 spike protein receptor bindi...

EntireName: Focused refinement of the SARS-CoV-2 spike protein receptor binding domain bound to neutralizing nanobodies WNb 2 and WNb 10
Components
  • Complex: Focused refinement of the SARS-CoV-2 spike protein receptor binding domain bound to neutralizing nanobodies WNb 2 and WNb 10
    • Complex: SARS-CoV-2 spike protein receptor binding domain
      • Protein or peptide: Spike glycoprotein
    • Complex: neutralizing nanobodies WNb 2 and WNb 10
      • Protein or peptide: WNb 2
      • Protein or peptide: WNb 10

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Supramolecule #1: Focused refinement of the SARS-CoV-2 spike protein receptor bindi...

SupramoleculeName: Focused refinement of the SARS-CoV-2 spike protein receptor binding domain bound to neutralizing nanobodies WNb 2 and WNb 10
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: SARS-CoV-2 spike protein receptor binding domain

SupramoleculeName: SARS-CoV-2 spike protein receptor binding domain / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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Supramolecule #3: neutralizing nanobodies WNb 2 and WNb 10

SupramoleculeName: neutralizing nanobodies WNb 2 and WNb 10 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Vicugna pacos (alpaca)

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Macromolecule #1: Spike glycoprotein

MacromoleculeName: Spike glycoprotein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 152.31275 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGGEGLRASP RRRPLLPLQP RGCPRGDGCL RGGRGRAGFG FWRVTGGSSA SANHVHAFFF FLQLLGNVLV VVLSHHFGKE LRPSQAEFG TATMFVFLVL LPLVSSQCVN LTTRTQLPPA YTNSFTRGVY YPDKVFRSSV LHSTQDLFLP FFSNVTWFHA I HVSGTNGT ...String:
MGGEGLRASP RRRPLLPLQP RGCPRGDGCL RGGRGRAGFG FWRVTGGSSA SANHVHAFFF FLQLLGNVLV VVLSHHFGKE LRPSQAEFG TATMFVFLVL LPLVSSQCVN LTTRTQLPPA YTNSFTRGVY YPDKVFRSSV LHSTQDLFLP FFSNVTWFHA I HVSGTNGT KRFDNPVLPF NDGVYFASTE KSNIIRGWIF GTTLDSKTQS LLIVNNATNV VIKVCEFQFC NDPFLGVYYH KN NKSWMES EFRVYSSANN CTFEYVSQPF LMDLEGKQGN FKNLREFVFK NIDGYFKIYS KHTPINLVRD LPQGFSALEP LVD LPIGIN ITRFQTLLAL HRSYLTPGDS SSGWTAGAAA YYVGYLQPRT FLLKYNENGT ITDAVDCALD PLSETKCTLK SFTV EKGIY QTSNFRVQPT ESIVRFPNIT NLCPFGEVFN ATRFASVYAW NRKRISNCVA DYSVLYNSAS FSTFKCYGVS PTKLN DLCF TNVYADSFVI RGDEVRQIAP GQTGKIADYN YKLPDDFTGC VIAWNSNNLD SKVGGNYNYL YRLFRKSNLK PFERDI STE IYQAGSTPCN GVEGFNCYFP LQSYGFQPTN GVGYQPYRVV VLSFELLHAP ATVCGPKKST NLVKNKCVNF NFNGLTG TG VLTESNKKFL PFQQFGRDIA DTTDAVRDPQ TLEILDITPC SFGGVSVITP GTNTSNQVAV LYQDVNCTEV PVAIHADQ L TPTWRVYSTG SNVFQTRAGC LIGAEHVNNS YECDIPIGAG ICASYQTQTN SPGSASSVAS QSIIAYTMSL GAENSVAYS NNSIAIPTNF TISVTTEILP VSMTKTSVDC TMYICGDSTE CSNLLLQYGS FCTQLNRALT GIAVEQDKNT QEVFAQVKQI YKTPPIKDF GGFNFSQILP DPSKPSKRSP IEDLLFNKVT LADAGFIKQY GDCLGDIAAR DLICAQKFNG LTVLPPLLTD E MIAQYTSA LLAGTITSGW TFGAGPALQI PFPMQMAYRF NGIGVTQNVL YENQKLIANQ FNSAIGKIQD SLSSTPSALG KL QDVVNQN AQALNTLVKQ LSSNFGAISS VLNDILSRLD PPEAEVQIDR LITGRLQSLQ TYVTQQLIRA AEIRASANLA ATK MSECVL GQSKRVDFCG KGYHLMSFPQ SAPHGVVFLH VTYVPAQEKN FTTAPAICHD GKAHFPREGV FVSNGTHWFV TQRN FYEPQ IITTDNTFVS GNCDVVIGIV NNTVYDPLQP ELDSFKEELD KYFKNHTSPD VDLGDISGIN ASVVNIQKEI DRLNE VAKN LNESLIDLQE LGKYEQGSGY IPEAPRDGQA YVRKDGEWVL LSTFLGRSLE VLFQGPGHHH HHHHHSAWSH PQFEKG GGS GGGGSGGSAW SHPQFEK

UniProtKB: Spike glycoprotein

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Macromolecule #2: WNb 2

MacromoleculeName: WNb 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Vicugna pacos (alpaca)
Molecular weightTheoretical: 14.106564 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLQESGGG LVQPGGSLRL SCAVSGFTLD YYAIGWFRQA PGKEREGVSC ISSSGGNTKY ADSVKGRFTA SRDNAKNTFY LQMNSLKPE DTAVYYCAAI AATYYSGSYY FQCPHDGMDY WGKGTQVTVS S

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Macromolecule #3: WNb 10

MacromoleculeName: WNb 10 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Vicugna pacos (alpaca)
Molecular weightTheoretical: 13.537003 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLQESGGG LVQPGGSLRL SCAASGFTFR RYLMGWARQV PGKGLEWVSG IYSDGSTYYA DSVKGRFTIS RDNAKNTVYL QMNSLKPED TAVYYCAKDR MDGSTWPERD FGSWGQGTQV TVSS

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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
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 55.9 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 151630
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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