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- EMDB-26200: Cryo-EM structure of SARS-CoV-2 spike in complex with FSR22, an a... -

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Basic information

Entry
Database: EMDB / ID: EMD-26200
TitleCryo-EM structure of SARS-CoV-2 spike in complex with FSR22, an anti-SARS-CoV-2 DARPin
Map data
Sample
  • Complex: DARPin FSR22 in complex with SARS-CoV-2 spike
    • Protein or peptide: Spike glycoproteinSpike protein
    • Protein or peptide: DARPin FSR22
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
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 / Attachment and Entry / membrane fusion / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / receptor ligand activity / host cell surface receptor binding / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / virion attachment to host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell plasma membrane / virion membrane / membrane / identical protein binding / 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 / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike glycoprotein, betacoronavirus / 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 ...Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike glycoprotein, betacoronavirus / 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 2 (HR2) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Spike glycoprotein S2 superfamily, coronavirus / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2 / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal
Similarity search - Domain/homology
Biological speciesSevere acute respiratory syndrome coronavirus 2 / Escherichia phage EcSzw-2Escherichia coli (virus)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.51 Å
AuthorsKwon YD / Gorman J / Kwong PD
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)HSSN261200800001E United States
CitationJournal: Nat Chem Biol / Year: 2023
Title: A potent and broad neutralization of SARS-CoV-2 variants of concern by DARPins.
Authors: Vikas Chonira / Young D Kwon / Jason Gorman / James Brett Case / Zhiqiang Ku / Rudo Simeon / Ryan G Casner / Darcy R Harris / Adam S Olia / Tyler Stephens / Lawrence Shapiro / Michael F ...Authors: Vikas Chonira / Young D Kwon / Jason Gorman / James Brett Case / Zhiqiang Ku / Rudo Simeon / Ryan G Casner / Darcy R Harris / Adam S Olia / Tyler Stephens / Lawrence Shapiro / Michael F Bender / Hannah Boyd / I-Ting Teng / Yaroslav Tsybovsky / Florian Krammer / Ningyan Zhang / Michael S Diamond / Peter D Kwong / Zhiqiang An / Zhilei Chen /
Abstract: We report the engineering and selection of two synthetic proteins-FSR16m and FSR22-for the possible treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. FSR16m and ...We report the engineering and selection of two synthetic proteins-FSR16m and FSR22-for the possible treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. FSR16m and FSR22 are trimeric proteins composed of DARPin SR16m or SR22 fused with a T4 foldon. Despite selection by a spike protein from a now historical SARS-CoV-2 strain, FSR16m and FSR22 exhibit broad-spectrum neutralization of SARS-CoV-2 strains, inhibiting authentic B.1.351, B.1.617.2 and BA.1.1 viruses, with respective IC values of 3.4, 2.2 and 7.4 ng ml for FSR16m. Cryo-EM structures revealed that these DARPins recognize a region of the receptor-binding domain (residues 456, 475, 486, 487 and 489) overlapping a critical portion of the angiotensin-converting enzyme 2 (ACE2)-binding surface. K18-hACE2 transgenic mice inoculated with B.1.617.2 and receiving intranasally administered FSR16m showed less weight loss and 10-100-fold lower viral burden in upper and lower respiratory tracts. The strong and broad neutralization potency makes FSR16m and FSR22 promising candidates for the prevention and treatment of infection by SARS-CoV-2.
History
DepositionFeb 15, 2022-
Header (metadata) releaseDec 7, 2022-
Map releaseDec 7, 2022-
UpdateMar 15, 2023-
Current statusMar 15, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26200.png

Downloads & links

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Map

FileDownload / File: emd_26200.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.87 Å/pix.
x 512 pix.
= 446.976 Å		0.87 Å/pix.
x 512 pix.
= 446.976 Å		0.87 Å/pix.
x 512 pix.
= 446.976 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.873 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.07
Minimum - Maximum-0.27166995 - 0.66456896
Average (Standard dev.)0.00011268316 (±0.017255064)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 446.976 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : DARPin FSR22 in complex with SARS-CoV-2 spike

EntireName: DARPin FSR22 in complex with SARS-CoV-2 spike
Components
  • Complex: DARPin FSR22 in complex with SARS-CoV-2 spike
    • Protein or peptide: Spike glycoproteinSpike protein
    • Protein or peptide: DARPin FSR22
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: DARPin FSR22 in complex with SARS-CoV-2 spike

SupramoleculeName: DARPin FSR22 in complex with SARS-CoV-2 spike / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#2
Details: FSR22, a trimer of three DARPin molecules formed by foldon at its N-terminus
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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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: 138.236828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QCVNLTTRTQ LPPAYTNSFT RGVYYPDKVF RSSVLHSTQD LFLPFFSNVT WFHAIHVSGT NGTKRFDNPV LPFNDGVYFA STEKSNIIR GWIFGTTLDS KTQSLLIVNN ATNVVIKVCE FQFCNDPFLG VYYHKNNKSW MESEFRVYSS ANNCTFEYVS Q PFLMDLEG ...String:
QCVNLTTRTQ LPPAYTNSFT RGVYYPDKVF RSSVLHSTQD LFLPFFSNVT WFHAIHVSGT NGTKRFDNPV LPFNDGVYFA STEKSNIIR GWIFGTTLDS KTQSLLIVNN ATNVVIKVCE FQFCNDPFLG VYYHKNNKSW MESEFRVYSS ANNCTFEYVS Q PFLMDLEG KQGNFKNLRE FVFKNIDGYF KIYSKHTPIN LVRDLPQGFS ALEPLVDLPI GINITRFQTL LALHRSYLTP GD SSSGWTA GAAAYYVGYL QPRTFLLKYN ENGTITDAVD CALDPLSETK CTLKSFTVEK GIYQTSNFRV QPTESIVRFP NIT NLCPFG EVFNATRFAS VYAWNRKRIS NCVADYSVLY NSASFSTFKC YGVSPTKLND LCFTNVYADS FVIRGDEVRQ IAPG QTGKI ADYNYKLPDD FTGCVIAWNS NNLDSKVGGN YNYLYRLFRK SNLKPFERDI STEIYQAGST PCNGVEGFNC YFPLQ SYGF QPTNGVGYQP YRVVVLSFEL LHAPATVCGP KKSTNLVKNK CVNFNFNGLT GTGVLTESNK KFLPFQQFGR DIADTT DAV RDPQTLEILD ITPCSFGGVS VITPGTNTSN QVAVLYQDVN CTEVPVAIHA DQLTPTWRVY STGSNVFQTR AGCLIGA EH VNNSYECDIP IGAGICASYQ TQTNSPGSAS SVASQSIIAY TMSLGAENSV AYSNNSIAIP TNFTISVTTE ILPVSMTK T SVDCTMYICG DSTECSNLLL QYGSFCTQLN RALTGIAVEQ DKNTQEVFAQ VKQIYKTPPI KDFGGFNFSQ ILPDPSKPS KRSPIEDLLF NKVTLADAGF IKQYGDCLGD IAARDLICAQ KFNGLTVLPP LLTDEMIAQY TSALLAGTIT SGWTFGAGPA LQIPFPMQM AYRFNGIGVT QNVLYENQKL IANQFNSAIG KIQDSLSSTP SALGKLQDVV NQNAQALNTL VKQLSSNFGA I SSVLNDIL SRLDPPEAEV QIDRLITGRL QSLQTYVTQQ LIRAAEIRAS ANLAATKMSE CVLGQSKRVD FCGKGYHLMS FP QSAPHGV VFLHVTYVPA QEKNFTTAPA ICHDGKAHFP REGVFVSNGT HWFVTQRNFY EPQIITTDNT FVSGNCDVVI GIV NNTVYD PLQPELDSFK EELDKYFKNH TSPDVDLGDI SGINASVVNI QKEIDRLNEV AKNLNESLID LQELGKYEQG SGYI PEAPR DGQAYVRKDG EWVLLSTFLG RSLEVLFQGP GHHHHHHHHS AW

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Macromolecule #2: DARPin FSR22

MacromoleculeName: DARPin FSR22 / type: protein_or_peptide / ID: 2 / Details: 3 darpin molecules linked by foldon / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Escherichia phage EcSzw-2Escherichia coli (virus)
Molecular weightTheoretical: 23.83558 KDa
SequenceString: MGSSHHHHHH SSGMEQKLIS EEDLDGYIPE APRDGQAYVR KDGEWVLLST FLGGGGSLQG GGGSLQGSDL GKKLLEAARA GQDDEVRIL MANGADVNAC DPSGITPLHL AADKGHLEIV EVLLKYGADV NAMDVWGRTP LHLAAFTGHL EIVEVLLKYG A DVNACDLN ...String:
MGSSHHHHHH SSGMEQKLIS EEDLDGYIPE APRDGQAYVR KDGEWVLLST FLGGGGSLQG GGGSLQGSDL GKKLLEAARA GQDDEVRIL MANGADVNAC DPSGITPLHL AADKGHLEIV EVLLKYGADV NAMDVWGRTP LHLAAFTGHL EIVEVLLKYG A DVNACDLN GYTPLHLAAG RGHLEIVEVL LKNGAGVNAQ DKFGKTAFDI SIDNGNEDLA EILQSSS

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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: 18 / 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

Concentration0.5 mg/mL
BufferpH: 7.4 / Details: 10 mM HEPES, 7.4, 150 mM NaCl
GridModel: C-flat / Material: COPPER / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.25 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.2 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 417461
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7bno

Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3)
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.51 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3) / Number images used: 18892

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Atomic model buiding 1

Initial modelPDB ID:

7bno

RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 134 / Target criteria: CC
Output model

PDB-7tyz:
Cryo-EM structure of SARS-CoV-2 spike in complex with FSR22, an anti-SARS-CoV-2 DARPin

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