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- PDB-8rj7: The crystal structure of the SARS-CoV-2 receptor binding domain i... -

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Basic information

Entry
Database: PDB / ID: 8rj7
TitleThe crystal structure of the SARS-CoV-2 receptor binding domain in complex with the neutralizing nanobody 1.29
Components
  • Camel-derived nanobody 1.29
  • Spike protein S1
KeywordsANTIVIRAL PROTEIN / coronavirus / COVID-19 / RBD / SARS-CoV-2 / spike / nanobodies / neutralization / VIRAL PROTEIN
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 / entry receptor-mediated virion attachment to host cell / membrane fusion / 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, 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
LYSINE / Spike glycoprotein
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
Camelus dromedarius (Arabian camel)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsCasasnovas, J.M. / Fernandez, L.A. / Silva, K.
Funding support Spain, 1items
OrganizationGrant numberCountry
Ministerio de Ciencia e Innovacion (MCIN)202020E079 Spain
Citation
Journal: To Be Published
Title: The crystal structure of the SARS-CoV-2 receptor binding domain in complex with the neutralizing nanobody 1.29
Authors: Casasnovas, J.M. / Fernandez, L.A. / Silva, K.
#1: Journal: Front Immunol / Year: 2022
Title: Nanobodies Protecting From Lethal SARS-CoV-2 Infection Target Receptor Binding Epitopes Preserved in Virus Variants Other Than Omicron.
Authors: José M Casasnovas / Yago Margolles / María A Noriega / María Guzmán / Rocío Arranz / Roberto Melero / Mercedes Casanova / Juan Alberto Corbera / Nereida Jiménez-de-Oya / Pablo ...Authors: José M Casasnovas / Yago Margolles / María A Noriega / María Guzmán / Rocío Arranz / Roberto Melero / Mercedes Casanova / Juan Alberto Corbera / Nereida Jiménez-de-Oya / Pablo Gastaminza / Urtzi Garaigorta / Juan Carlos Saiz / Miguel Ángel Martín-Acebes / Luis Ángel Fernández /
Abstract: The emergence of SARS-CoV-2 variants that escape from immune neutralization are challenging vaccines and antibodies developed to stop the COVID-19 pandemic. Thus, it is important to establish ...The emergence of SARS-CoV-2 variants that escape from immune neutralization are challenging vaccines and antibodies developed to stop the COVID-19 pandemic. Thus, it is important to establish therapeutics directed toward multiple or specific SARS-CoV-2 variants. The envelope spike (S) glycoprotein of SARS-CoV-2 is the key target of neutralizing antibodies (Abs). We selected a panel of nine nanobodies (Nbs) from dromedary camels immunized with the receptor-binding domain (RBD) of the S, and engineered Nb fusions as humanized heavy chain Abs (hcAbs). Nbs and derived hcAbs bound with subnanomolar or picomolar affinities to the S and its RBD, and S-binding cross-competition clustered them in two different groups. Most of the hcAbs hindered RBD binding to its human ACE2 (hACE2) receptor, blocked cell entry of viruses pseudotyped with the S protein and neutralized SARS-CoV-2 infection in cell cultures. Four potent neutralizing hcAbs prevented the progression to lethal SARS-CoV-2 infection in hACE2-transgenic mice, demonstrating their therapeutic potential. Cryo-electron microscopy identified Nb binding epitopes in and out the receptor binding motif (RBM), and showed different ways to prevent virus binding to its cell entry receptor. The Nb binding modes were consistent with its recognition of SARS-CoV-2 RBD variants; mono and bispecific hcAbs efficiently bound all variants of concern except omicron, which emphasized the immune escape capacity of this latest variant.
History
DepositionDec 20, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Spike protein S1
C: Spike protein S1
E: Spike protein S1
G: Spike protein S1
B: Camel-derived nanobody 1.29
D: Camel-derived nanobody 1.29
F: Camel-derived nanobody 1.29
H: Camel-derived nanobody 1.29
I: Spike protein S1
J: Camel-derived nanobody 1.29
hetero molecules


Theoretical massNumber of molelcules
Total (without water)182,10921
Polymers180,37610
Non-polymers1,73411
Water15,979887
1
A: Spike protein S1
B: Camel-derived nanobody 1.29
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4885
Polymers36,0752
Non-polymers4133
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2310 Å2
ΔGint-17 kcal/mol
Surface area14720 Å2
2
C: Spike protein S1
D: Camel-derived nanobody 1.29
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5405
Polymers36,0752
Non-polymers4643
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-11 kcal/mol
Surface area15210 Å2
3
E: Spike protein S1
F: Camel-derived nanobody 1.29
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3924
Polymers36,0752
Non-polymers3172
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1960 Å2
ΔGint0 kcal/mol
Surface area14700 Å2
4
G: Spike protein S1
H: Camel-derived nanobody 1.29
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3924
Polymers36,0752
Non-polymers3172
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1830 Å2
ΔGint-1 kcal/mol
Surface area15030 Å2
5
I: Spike protein S1
J: Camel-derived nanobody 1.29
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2963
Polymers36,0752
Non-polymers2211
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2380 Å2
ΔGint-16 kcal/mol
Surface area14570 Å2
Unit cell
Length a, b, c (Å)89.164, 89.164, 200.247
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number145
Space group name H-MP32
Space group name HallP32
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3

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Components

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Protein / Antibody / Sugars , 3 types, 15 molecules ACEGIBDFHJ

#1: Protein
Spike protein S1


Mass: 22726.562 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: S, 2 / Plasmid: Flag-MCS-pcDNA3.1 / Cell (production host): epithelial / Cell line (production host): HEK293 / Organ (production host): kidney / Production host: Homo sapiens (human) / Tissue (production host): Embryo / References: UniProt: P0DTC2
#2: Antibody
Camel-derived nanobody 1.29


Mass: 13348.559 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Camelus dromedarius (Arabian camel) / Plasmid: Flag-MCS-pcDNA3.1 / Cell (production host): epithelial / Cell line (production host): HEK293F / Organ (production host): kidney / Production host: Homo sapiens (human) / Tissue (production host): Embryo
#3: 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.: 5 / Source method: obtained synthetically / Formula: C8H15NO6
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

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Non-polymers , 3 types, 893 molecules

#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-LYS / LYSINE


Type: L-peptide linking / Mass: 147.195 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H15N2O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 887 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
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: 2.55 Å3/Da / Density % sol: 51.72 % / Description: Triangular plates
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 15% PEG-3350, 100mM Bicine pH 9, 20 mM (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.97926 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 24, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97926 Å / Relative weight: 1
ReflectionResolution: 2.1→44.58 Å / Num. obs: 103348 / % possible obs: 99.4 % / Redundancy: 4.1 % / Biso Wilson estimate: 37.89 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.079 / Rpim(I) all: 0.09 / Net I/σ(I): 8.4
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.749 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 5173 / CC1/2: 0.56 / Rpim(I) all: 0.885 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→43.52 Å / SU ML: 0.2744 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 22.0894
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2215 5183 5.02 %
Rwork0.1811 98121 -
obs0.1831 103304 99.35 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.61 Å2
Refinement stepCycle: LAST / Resolution: 2.1→43.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12145 0 104 887 13136
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007412545
X-RAY DIFFRACTIONf_angle_d0.852217059
X-RAY DIFFRACTIONf_chiral_restr0.05411815
X-RAY DIFFRACTIONf_plane_restr0.00722233
X-RAY DIFFRACTIONf_dihedral_angle_d6.29391779
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.120.29731820.26043389X-RAY DIFFRACTION99.8
2.12-2.150.31821950.2613215X-RAY DIFFRACTION99.8
2.15-2.180.26251550.24133381X-RAY DIFFRACTION99.75
2.18-2.20.3141740.23993190X-RAY DIFFRACTION99.94
2.2-2.230.27762020.22713313X-RAY DIFFRACTION99.94
2.23-2.260.26572300.22613157X-RAY DIFFRACTION99.85
2.26-2.290.27261590.21863362X-RAY DIFFRACTION99.94
2.29-2.330.26812400.20943179X-RAY DIFFRACTION99.74
2.33-2.370.2561580.21493273X-RAY DIFFRACTION99.45
2.37-2.40.24731960.21283269X-RAY DIFFRACTION99.43
2.4-2.450.30881610.21243258X-RAY DIFFRACTION99.48
2.45-2.490.27441620.21953315X-RAY DIFFRACTION99.51
2.49-2.540.26241800.22193289X-RAY DIFFRACTION99.94
2.54-2.590.25721840.21943232X-RAY DIFFRACTION99.94
2.59-2.650.26831420.21353347X-RAY DIFFRACTION99.83
2.65-2.710.23371700.19513328X-RAY DIFFRACTION99.94
2.71-2.770.26531680.19743290X-RAY DIFFRACTION99.8
2.78-2.850.2541950.20763231X-RAY DIFFRACTION99.54
2.85-2.930.27221380.19433246X-RAY DIFFRACTION99.06
2.93-3.030.22921690.19773294X-RAY DIFFRACTION99.06
3.03-3.140.25671600.20473265X-RAY DIFFRACTION99.51
3.14-3.260.25541680.1933303X-RAY DIFFRACTION99.43
3.26-3.410.23031330.18973327X-RAY DIFFRACTION99.37
3.41-3.590.22971470.16983285X-RAY DIFFRACTION99.16
3.59-3.820.16681580.16533206X-RAY DIFFRACTION98.39
3.82-4.110.19161600.14313254X-RAY DIFFRACTION98.16
4.11-4.520.17621690.13673243X-RAY DIFFRACTION98.61
4.52-5.180.12591150.13973309X-RAY DIFFRACTION98.33
5.18-6.520.18652300.16823147X-RAY DIFFRACTION97.8
6.52-43.520.2011830.16463224X-RAY DIFFRACTION98.07

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