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- PDB-7kn7: Crystal structure of SARS-CoV-2 receptor binding domain complexed... -

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Basic information

Entry
Database: PDB / ID: 7kn7
TitleCrystal structure of SARS-CoV-2 receptor binding domain complexed with nanobody VHH W and antibody Fab CC12.3
Components
  • CC12.3 Fab heavy chain
  • CC12.3 Fab light chain
  • Spike protein S1
  • VHH W
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / SARS-CoV-2 / Nanobody / Spike / Coronavirus / COVID-19 / IMMUNE SYSTEM / Nanobody-antigen complex / single-domain antibody / Antibody / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


symbiont-mediated disruption of host tissue / Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / viral translation / host extracellular space / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion ...symbiont-mediated disruption of host tissue / Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / viral translation / host extracellular space / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / membrane fusion / entry receptor-mediated virion attachment to host cell / Attachment and Entry / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / receptor ligand activity / endocytosis involved in viral entry into host cell / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / symbiont entry into host cell / 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, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / 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 (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, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / 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 / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Spike glycoprotein S2 superfamily, coronavirus / 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, coronavirus / Coronavirus spike glycoprotein S2 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Biological speciesSevere acute respiratory syndrome coronavirus 2
Vicugna pacos (alpaca)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.73 Å
AuthorsLiu, H. / Yuan, M. / Zhu, X. / Wu, N.C. / Wilson, I.A.
Funding support United States, 2items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationOPP1170236 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI139445 United States
CitationJournal: Science / Year: 2021
Title: Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape.
Authors: Paul-Albert Koenig / Hrishikesh Das / Hejun Liu / Beate M Kümmerer / Florian N Gohr / Lea-Marie Jenster / Lisa D J Schiffelers / Yonas M Tesfamariam / Miki Uchima / Jennifer D Wuerth / Karl ...Authors: Paul-Albert Koenig / Hrishikesh Das / Hejun Liu / Beate M Kümmerer / Florian N Gohr / Lea-Marie Jenster / Lisa D J Schiffelers / Yonas M Tesfamariam / Miki Uchima / Jennifer D Wuerth / Karl Gatterdam / Natalia Ruetalo / Maria H Christensen / Caroline I Fandrey / Sabine Normann / Jan M P Tödtmann / Steffen Pritzl / Leo Hanke / Jannik Boos / Meng Yuan / Xueyong Zhu / Jonathan L Schmid-Burgk / Hiroki Kato / Michael Schindler / Ian A Wilson / Matthias Geyer / Kerstin U Ludwig / B Martin Hällberg / Nicholas C Wu / Florian I Schmidt /
Abstract: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost ...The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes. On the basis of these structures, we engineered multivalent nanobodies with more than 100 times the neutralizing activity of monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor binding competition, whereas other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion and rendered the virions noninfectious.
History
DepositionNov 4, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2021Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation_author.identifier_ORCID
Revision 1.3Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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 W
H: CC12.3 Fab heavy chain
L: CC12.3 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,3115
Polymers88,0904
Non-polymers2211
Water00
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)192.400, 105.879, 55.746
Angle α, β, γ (deg.)90.000, 101.858, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

#1: Protein Spike protein S1


Mass: 26095.348 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: S, 2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P0DTC2
#2: Antibody VHH W


Mass: 15272.628 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Vicugna pacos (alpaca) / Production host: Escherichia coli (E. coli) / Strain (production host): WK6
#3: Antibody CC12.3 Fab heavy chain


Mass: 23377.150 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 CC12.3 Fab light chain


Mass: 23344.883 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: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestY
Has protein modificationY

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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: 3.15 Å3/Da / Density % sol: 61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 1.0 M Li-chloride, 10% PEG-6000, 0.1 M Bicine pH 9.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.03317 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03317 Å / Relative weight: 1
ReflectionResolution: 2.73→50 Å / Num. obs: 28107 / % possible obs: 98.1 % / Redundancy: 5.3 % / Biso Wilson estimate: 46.18 Å2 / CC1/2: 0.969 / Rmerge(I) obs: 0.181 / Rpim(I) all: 0.084 / Net I/σ(I): 9.3
Reflection shellResolution: 2.73→2.8 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.585 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1330 / CC1/2: 0.681 / Rpim(I) all: 0.37 / % possible all: 93

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
HKL-2000data reduction
HKL-2000data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6XC7, 7JMW, 6WAQ

6xc7

7jmw

6waq


Resolution: 2.73→49.18 Å / SU ML: 0.3802 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 27.1305
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2409 1475 5.25 %
Rwork0.2033 26601 -
obs0.2054 28076 96.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 49.36 Å2
Refinement stepCycle: LAST / Resolution: 2.73→49.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5685 0 14 0 5699
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00325838
X-RAY DIFFRACTIONf_angle_d0.74577934
X-RAY DIFFRACTIONf_chiral_restr0.0468863
X-RAY DIFFRACTIONf_plane_restr0.00381028
X-RAY DIFFRACTIONf_dihedral_angle_d11.19743416
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.73-2.820.35961020.28921974X-RAY DIFFRACTION79
2.82-2.920.27921480.27892457X-RAY DIFFRACTION98.3
2.92-3.040.37481380.28382453X-RAY DIFFRACTION99.81
3.04-3.180.31561410.25782474X-RAY DIFFRACTION99.89
3.18-3.350.32941230.24432521X-RAY DIFFRACTION99.77
3.35-3.560.26621320.22652434X-RAY DIFFRACTION97.05
3.56-3.830.27241280.20482380X-RAY DIFFRACTION95.91
3.83-4.210.23291450.18042370X-RAY DIFFRACTION94.73
4.21-4.820.15491540.1472478X-RAY DIFFRACTION99.66
4.82-6.080.18341270.16012521X-RAY DIFFRACTION99.74
6.08-49.180.21071370.18792539X-RAY DIFFRACTION99.11
Refinement TLS params.Method: refined / Origin x: 43.8301883298 Å / Origin y: 10.9088686176 Å / Origin z: 23.6498151984 Å
111213212223313233
T0.166623170455 Å20.0241501007427 Å20.0268220331355 Å2-0.180309071785 Å20.000672011513834 Å2--0.18198581429 Å2
L0.344827501539 °2-0.165869523824 °20.455403618694 °2-0.329445098545 °2-0.273904931523 °2--0.545749175106 °2
S0.0188515402194 Å °0.00272470100257 Å °0.0156845758645 Å °-0.00489398318721 Å °-0.0384487939992 Å °0.0250928451059 Å °-0.00266974987831 Å °0.0249513697239 Å °0.000228132743229 Å °
Refinement TLS groupSelection details: all

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