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- PDB-8cwv: Crystal structure of SARS-CoV-2 spike protein receptor-binding do... -

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Basic information

Entry
Database: PDB / ID: 8cwv
TitleCrystal structure of SARS-CoV-2 spike protein receptor-binding domain in complex with a cross-neutralizing nanobody 2-31 and a human antibody CC12.1 Fab
Components
  • CC12.1 Fab heavy chain
  • CC12.1 Fab light chain
  • Spike protein S1
  • VHH 2-31
KeywordsIMMUNE SYSTEM / cross-neutralizing antibody / nanobody / SARS-CoV-2 / Sarbecovirus / VHH / CC12.1
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 / host cell endoplasmic reticulum-Golgi intermediate compartment membrane ...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 / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / entry receptor-mediated virion attachment to host cell / 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
Lama glama (llama)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsLiu, H. / Wilson, I.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationINV-004923 United States
CitationJournal: Cell Rep / Year: 2022
Title: Superimmunity by pan-sarbecovirus nanobodies.
Authors: Yufei Xiang / Wei Huang / Hejun Liu / Zhe Sang / Sham Nambulli / Jérôme Tubiana / Kevin L Williams / W Paul Duprex / Dina Schneidman-Duhovny / Ian A Wilson / Derek J Taylor / Yi Shi /
Abstract: Vaccine boosters and infection can facilitate the development of SARS-CoV-2 antibodies with improved potency and breadth. Here, we observe superimmunity in a camelid extensively immunized with the ...Vaccine boosters and infection can facilitate the development of SARS-CoV-2 antibodies with improved potency and breadth. Here, we observe superimmunity in a camelid extensively immunized with the SARS-CoV-2 receptor-binding domain (RBD). We rapidly isolate a large repertoire of specific ultra-high-affinity nanobodies that bind strongly to all known sarbecovirus clades using integrative proteomics. These pan-sarbecovirus nanobodies (psNbs) are highly effective against SARS-CoV and SARS-CoV-2 variants, including Omicron, with the best median neutralization potency at single-digit nanograms per milliliter. A highly potent, inhalable, and bispecific psNb (PiN-31) is also developed. Structural determinations of 13 psNbs with the SARS-CoV-2 spike or RBD reveal five epitope classes, providing insights into the mechanisms and evolution of their broad activities. The highly evolved psNbs target small, flat, and flexible epitopes that contain over 75% of conserved RBD surface residues. Their potencies are strongly and negatively correlated with the distance of the epitopes from the receptor binding sites.
History
DepositionMay 19, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2022Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Spike protein S1
B: VHH 2-31
H: CC12.1 Fab heavy chain
L: CC12.1 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,7175
Polymers87,1464
Non-polymers5711
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.310, 142.024, 149.367
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Spike protein S1


Mass: 23104.867 Da / Num. of mol.: 1 / Fragment: Receptor binding domain, UNP residues 333-530
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P0DTC2
#2: Antibody VHH 2-31


Mass: 17221.012 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama)
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
#3: Antibody CC12.1 Fab heavy chain


Mass: 23178.928 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Mus musculus (house mouse)
#4: Antibody CC12.1 Fab light chain


Mass: 23641.365 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Mus musculus (house mouse)
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-1-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.71 Å3/Da / Density % sol: 54.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 40% MPD, 0.1M cacodylate pH 6.5 5% (w/v) PEG-8000, final pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 31, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 27562 / % possible obs: 84 % / Redundancy: 3.3 % / Biso Wilson estimate: 43.57 Å2 / Rmerge(I) obs: 0.147 / Rpim(I) all: 0.088 / Rrim(I) all: 0.173 / Χ2: 0.865 / Net I/σ(I): 4.3 / Num. measured all: 90065
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.5-2.543.11.1213440.4590.71.3320.70281.9
2.54-2.5931.01313260.5250.6261.20.7282.4
2.59-2.642.90.89413060.5490.5671.0660.71881.8
2.64-2.693.10.82113760.6540.5070.9740.74282.4
2.69-2.753.10.7513090.6740.4570.8850.76282
2.75-2.823.30.64113370.7150.3810.7520.78882.9
2.82-2.893.40.5413920.8110.3120.6280.7884.6
2.89-2.963.30.46113270.8740.2690.5380.85282.8
2.96-3.053.30.36213690.8590.2190.4270.87284.2
3.05-3.153.30.31113780.9110.1880.3670.95384.3
3.15-3.2630.25513650.9050.1590.3031.0384.2
3.26-3.393.30.21913510.9210.1330.2591.04983.2
3.39-3.553.50.18614030.9450.1090.2171.04784.6
3.55-3.733.50.1613690.9570.0940.1871.04984.4
3.73-3.973.40.14214190.9630.0870.1681.07985.6
3.97-4.273.10.12113720.9610.0780.1451.00684.1
4.27-4.73.30.10514200.9760.0640.1240.97185.2
4.7-5.383.50.10114360.9770.0590.1180.82686.6
5.38-6.783.40.10214500.9380.0620.1210.74385.7
6.78-503.70.08815130.9780.050.1020.60285.5

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
HKL-2000data scaling
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7JMW; 7KN5

7jmw

7kn5


Resolution: 2.51→42.78 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 30.28 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.264 1174 5.03 %
Rwork0.2377 22179 -
obs0.239 23353 71.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 125.56 Å2 / Biso mean: 46.0899 Å2 / Biso min: 19.83 Å2
Refinement stepCycle: final / Resolution: 2.51→42.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5744 0 38 0 5782
Biso mean--93.9 --
Num. residues----754
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.51-2.620.3816340.395182385721
2.62-2.760.35321030.3191945204851
2.76-2.940.35421540.3042973312778
2.94-3.160.3271990.28413175337482
3.16-3.480.28841670.25913219338683
3.48-3.980.25961680.23013292346084
3.98-5.020.22911660.1963298346484
5.02-42.780.21581830.21333454363785
Refinement TLS params.Method: refined / Origin x: 6.071 Å / Origin y: 36.1072 Å / Origin z: 0.7865 Å
111213212223313233
T0.1834 Å2-0.017 Å2-0.0355 Å2-0.2874 Å2-0.0344 Å2--0.2418 Å2
L0.424 °20.375 °2-0.3891 °2-0.9415 °2-0.5473 °2--0.5521 °2
S0.0574 Å °0.0117 Å °0.0657 Å °0.061 Å °-0.0493 Å °0.0564 Å °-0.041 Å °0.082 Å °-0.0052 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA334 - 630
2X-RAY DIFFRACTION1allB2 - 111
3X-RAY DIFFRACTION1allH2 - 215
4X-RAY DIFFRACTION1allL1 - 213

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