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- EMDB-30484: P17-H014 Fab cocktail in complex with SARS-CoV-2 spike protein -

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Basic information

Entry
Database: EMDB / ID: EMD-30484
TitleP17-H014 Fab cocktail in complex with SARS-CoV-2 spike protein
Map data
Sample
  • Complex: H014 and P17 Fab cocktail in complex with SARS-CoV-2 spike protein
    • Complex: SARS-CoV-2 spike protein
      • Protein or peptide: Spike glycoprotein
    • Complex: P17 Fab
      • Protein or peptide: heavy chain of P17 Fab
      • Protein or peptide: light chain of P17 Fab
    • Complex: H014 Fab
      • Protein or peptide: light chain of H014 Fab
      • Protein or peptide: heavy chain of H014 Fab
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsCocktail / Complex / SARS-CoV-2 spike protein / Fab / 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 / receptor-mediated endocytosis of virus by host cell / membrane fusion / 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 / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / 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 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWang N / Wang X
CitationJournal: Cell Res / Year: 2021
Title: Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection.
Authors: Hangping Yao / Yao Sun / Yong-Qiang Deng / Nan Wang / Yongcong Tan / Na-Na Zhang / Xiao-Feng Li / Chao Kong / Yan-Peng Xu / Qi Chen / Tian-Shu Cao / Hui Zhao / Xintian Yan / Lei Cao / Zhe Lv ...Authors: Hangping Yao / Yao Sun / Yong-Qiang Deng / Nan Wang / Yongcong Tan / Na-Na Zhang / Xiao-Feng Li / Chao Kong / Yan-Peng Xu / Qi Chen / Tian-Shu Cao / Hui Zhao / Xintian Yan / Lei Cao / Zhe Lv / Dandan Zhu / Rui Feng / Nanping Wu / Wenhai Zhang / Yuhao Hu / Keda Chen / Rong-Rong Zhang / Qingyu Lv / Shihui Sun / Yunhua Zhou / Run Yan / Guan Yang / Xinglu Sun / Chanjuan Liu / Xiangyun Lu / Linfang Cheng / Hongying Qiu / Xing-Yao Huang / Tianhao Weng / Danrong Shi / Weidong Jiang / Junbin Shao / Lei Wang / Jie Zhang / Tao Jiang / Guojun Lang / Cheng-Feng Qin / Lanjuan Li / Xiangxi Wang /
Abstract: Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a ...Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.
History
DepositionAug 29, 2020-
Header (metadata) releaseDec 16, 2020-
Map releaseDec 16, 2020-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.008
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.008
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7cwn
  • Surface level: 0.008
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30484.png

Downloads & links

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Map

FileDownload / File: emd_30484.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 400 pix.
= 416. Å		1.04 Å/pix.
x 400 pix.
= 416. Å		1.04 Å/pix.
x 400 pix.
= 416. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00538 / Movie #1: 0.008
Minimum - Maximum-0.017884072 - 0.05824898
Average (Standard dev.)0.00007940772 (±0.0013636637)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 416.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z416.000416.000416.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ360360360
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0180.0580.000

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Supplemental data

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Sample components

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Entire : H014 and P17 Fab cocktail in complex with SARS-CoV-2 spike protein

EntireName: H014 and P17 Fab cocktail in complex with SARS-CoV-2 spike protein
Components
  • Complex: H014 and P17 Fab cocktail in complex with SARS-CoV-2 spike protein
    • Complex: SARS-CoV-2 spike protein
      • Protein or peptide: Spike glycoprotein
    • Complex: P17 Fab
      • Protein or peptide: heavy chain of P17 Fab
      • Protein or peptide: light chain of P17 Fab
    • Complex: H014 Fab
      • Protein or peptide: light chain of H014 Fab
      • Protein or peptide: heavy chain of H014 Fab
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: H014 and P17 Fab cocktail in complex with SARS-CoV-2 spike protein

SupramoleculeName: H014 and P17 Fab cocktail in complex with SARS-CoV-2 spike protein
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5

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Supramolecule #2: SARS-CoV-2 spike protein

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

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Supramolecule #3: P17 Fab

SupramoleculeName: P17 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: H014 Fab

SupramoleculeName: H014 Fab / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #4-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Spike glycoprotein

MacromoleculeName: Spike glycoprotein / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 141.297422 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS NVTWFHAIHV SGTNGTKRFD NPVLPFNDG VYFASTEKSN IIRGWIFGTT LDSKTQSLLI VNNATNVVIK VCEFQFCNDP FLGVYYHKNN KSWMESEFRV Y SSANNCTF ...String:
MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS NVTWFHAIHV SGTNGTKRFD NPVLPFNDG VYFASTEKSN IIRGWIFGTT LDSKTQSLLI VNNATNVVIK VCEFQFCNDP FLGVYYHKNN KSWMESEFRV Y SSANNCTF EYVSQPFLMD LEGKQGNFKN LREFVFKNID GYFKIYSKHT PINLVRDLPQ GFSALEPLVD LPIGINITRF QT LLALHRS YLTPGDSSSG WTAGAAAYYV GYLQPRTFLL KYNENGTITD AVDCALDPLS ETKCTLKSFT VEKGIYQTSN FRV QPTESI VRFPNITNLC PFGEVFNATR FASVYAWNRK RISNCVADYS VLYNSASFST FKCYGVSPTK LNDLCFTNVY ADSF VIRGD EVRQIAPGQT GKIADYNYKL PDDFTGCVIA WNSNNLDSKV GGNYNYLYRL FRKSNLKPFE RDISTEIYQA GSTPC NGVE GFNCYFPLQS YGFQPTNGVG YQPYRVVVLS FELLHAPATV CGPKKSTNLV KNKCVNFNFN GLTGTGVLTE SNKKFL PFQ QFGRDIADTT DAVRDPQTLE ILDITPCSFG GVSVITPGTN TSNQVAVLYQ DVNCTEVPVA IHADQLTPTW RVYSTGS NV FQTRAGCLIG AEHVNNSYEC DIPIGAGICA SYQTQTNSPR RARSVASQSI IAYTMSLGAE NSVAYSNNSI AIPTNFTI S VTTEILPVSM TKTSVDCTMY ICGDSTECSN LLLQYGSFCT QLNRALTGIA VEQDKNTQEV FAQVKQIYKT PPIKDFGGF NFSQILPDPS KPSKRSFIED LLFNKVTLAD AGFIKQYGDC LGDIAARDLI CAQKFNGLTV LPPLLTDEMI AQYTSALLAG TITSGWTFG AGAALQIPFA MQMAYRFNGI GVTQNVLYEN QKLIANQFNS AIGKIQDSLS STASALGKLQ DVVNQNAQAL N TLVKQLSS NFGAISSVLN DILSRLDKVE AEVQIDRLIT GRLQSLQTYV TQQLIRAAEI RASANLAATK MSECVLGQSK RV DFCGKGY HLMSFPQSAP HGVVFLHVTY VPAQEKNFTT APAICHDGKA HFPREGVFVS NGTHWFVTQR NFYEPQIITT DNT FVSGNC DVVIGIVNNT VYDPLQPELD SFKEELDKYF KNHTSPDVDL GDISGINASV VNIQKEIDRL NEVAKNLNES LIDL QELGK YEQYIKWPWY IWLGFIAGLI AIVMVTIMLC CMTSCCSCLK GCCSCGSCCK FDEDDSEPVL KGVKLHYT

UniProtKB: Spike glycoprotein

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Macromolecule #2: heavy chain of P17 Fab

MacromoleculeName: heavy chain of P17 Fab / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.764588 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QQLVESGGGV VQPGRSLRLS CAASGFTFSS YAMHWVRQAP GKGLEWVAVI SYDGSNKYYA DSVKGRFTIS RDNSKNTLYL QMNSLRAED TAVYYCARHA TLMNNKDIWG QGTLVTVSSA STKGPSVFPL APSGGTAALG CLVKDYFPEP VTVSWNSGAL T SGVHTFPA ...String:
QQLVESGGGV VQPGRSLRLS CAASGFTFSS YAMHWVRQAP GKGLEWVAVI SYDGSNKYYA DSVKGRFTIS RDNSKNTLYL QMNSLRAED TAVYYCARHA TLMNNKDIWG QGTLVTVSSA STKGPSVFPL APSGGTAALG CLVKDYFPEP VTVSWNSGAL T SGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KKVEP

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Macromolecule #3: light chain of P17 Fab

MacromoleculeName: light chain of P17 Fab / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.769176 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GDIQLTQSPS SLSASVGDRV TITCRASQSI SSYLNWYQQK PGKAPKLLIY AASSLQSGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYC QQSYSTPRTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S ESVTEQDS ...String:
GDIQLTQSPS SLSASVGDRV TITCRASQSI SSYLNWYQQK PGKAPKLLIY AASSLQSGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYC QQSYSTPRTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSTKSFN R

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Macromolecule #4: light chain of H014 Fab

MacromoleculeName: light chain of H014 Fab / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.99967 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: IVLTQSPFQS VSPKEKVTIT CRASQSISSN LHWYQQKPDQ SPKLLIKYAS QSISGIPSRF SGSGSGTDFT LTINSLEAED FGIYFCQQT NFWPYIFGQG TKLEILKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSE S VTEQDSKD ...String:
IVLTQSPFQS VSPKEKVTIT CRASQSISSN LHWYQQKPDQ SPKLLIKYAS QSISGIPSRF SGSGSGTDFT LTINSLEAED FGIYFCQQT NFWPYIFGQG TKLEILKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSE S VTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSTKSFNR

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Macromolecule #5: heavy chain of H014 Fab

MacromoleculeName: heavy chain of H014 Fab / type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.883549 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: VQLVQSGAEV KKPGATVKIS CKVSGYSFSN YYIHWVKQAP GKSLEWIGYI DPFNGGTSDN LKFKGAATLT ADTSTDTAYM ELSSLRSED TAVYYCARSE YDPYYVMDYW GQGTTVTVSS ASTKGPSVFP LAPSGGTAAL GCLVKDYFPE PVTVSWNSGA L TSGVHTFP ...String:
VQLVQSGAEV KKPGATVKIS CKVSGYSFSN YYIHWVKQAP GKSLEWIGYI DPFNGGTSDN LKFKGAATLT ADTSTDTAYM ELSSLRSED TAVYYCARSE YDPYYVMDYW GQGTTVTVSS ASTKGPSVFP LAPSGGTAAL GCLVKDYFPE PVTVSWNSGA L TSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEP

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 16 / 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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: RANDOM CONICAL TILT
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 175063
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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