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- PDB-7ttm: Crystal structure of potent neutralizing antibody 10-40 in comple... -

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Basic information

Entry
Database: PDB / ID: 7ttm
TitleCrystal structure of potent neutralizing antibody 10-40 in complex with Sarbecovirus bat SHC014 receptor-binding domain
Components
  • 1040 heavy chain
  • 1040 light chain
  • Spike protein S1
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / COVID-19 / SarbecoVirus / SCH014 RBD / Viral protein / Spike glycoprotein / Receptor Binding Protein / Neutralizing antibody / potent / 10-40 / Fab / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


host cell endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated virion attachment to host cell / 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 / host cell plasma membrane / virion membrane / membrane
Similarity search - Function
Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / 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 (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Biological speciesBat SARS-like coronavirus RsSHC014
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.24 Å
AuthorsReddem, E.R. / Shapiro, L.
Funding support China, 1items
OrganizationGrant numberCountry
Jack Ma Foundation China
CitationJournal: Sci Transl Med / Year: 2022
Title: An antibody class with a common CDRH3 motif broadly neutralizes sarbecoviruses.
Authors: Lihong Liu / Sho Iketani / Yicheng Guo / Eswar R Reddem / Ryan G Casner / Manoj S Nair / Jian Yu / Jasper F-W Chan / Maple Wang / Gabriele Cerutti / Zhiteng Li / Nicholas C Morano / Candace ...Authors: Lihong Liu / Sho Iketani / Yicheng Guo / Eswar R Reddem / Ryan G Casner / Manoj S Nair / Jian Yu / Jasper F-W Chan / Maple Wang / Gabriele Cerutti / Zhiteng Li / Nicholas C Morano / Candace D Castagna / Laura Corredor / Hin Chu / Shuofeng Yuan / Vincent Kwok-Man Poon / Chris Chun-Sing Chan / Zhiwei Chen / Yang Luo / Marcus Cunningham / Alejandro Chavez / Michael T Yin / David S Perlin / Moriya Tsuji / Kwok-Yung Yuen / Peter D Kwong / Zizhang Sheng / Yaoxing Huang / Lawrence Shapiro / David D Ho /
Abstract: The devastation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made clear the importance of pandemic preparedness. To address future zoonotic outbreaks due to related ...The devastation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made clear the importance of pandemic preparedness. To address future zoonotic outbreaks due to related viruses in the sarbecovirus subgenus, we identified a human monoclonal antibody, 10-40, that neutralized or bound all sarbecoviruses tested in vitro and protected against SARS-CoV-2 and SARS-CoV in vivo. Comparative studies with other receptor-binding domain (RBD)-directed antibodies showed 10-40 to have the greatest breadth against sarbecoviruses, suggesting that 10-40 is a promising agent for pandemic preparedness. Moreover, structural analyses on 10-40 and similar antibodies not only defined an epitope cluster in the inner face of the RBD that is well conserved among sarbecoviruses but also uncovered a distinct antibody class with a common CDRH3 motif. Our analyses also suggested that elicitation of this class of antibodies may not be overly difficult, an observation that bodes well for the development of a pan-sarbecovirus vaccine.
History
DepositionFeb 1, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 27, 2022Provider: repository / Type: Initial release
Revision 1.1May 4, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 8, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Oct 23, 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

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Assembly

Deposited unit
A: Spike protein S1
H: 1040 heavy chain
L: 1040 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,3206
Polymers73,6563
Non-polymers6643
Water1,964109
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5690 Å2
ΔGint-9 kcal/mol
Surface area28910 Å2
Unit cell
Length a, b, c (Å)72.433, 69.217, 81.853
Angle α, β, γ (deg.)90.000, 103.630, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Spike protein S1


Mass: 25860.971 Da / Num. of mol.: 1 / Fragment: receptor-binding domain (UNP residues 307-528)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bat SARS-like coronavirus RsSHC014 / Gene: S / Production host: Homo sapiens (human) / References: UniProt: U5WLK5
#2: Antibody 1040 heavy chain


Mass: 24537.410 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody 1040 light chain


Mass: 23257.518 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: 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.: 3 / 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 109 / Source method: isolated from a natural source / Formula: H2O
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: 2.71 Å3/Da / Density % sol: 54.57 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 0.1 M sodium citrate, pH 5.2, 28% PEG4000, 0.2 M ammonium acetate

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Data collection

DiffractionMean temperature: 110 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97911 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 27, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97911 Å / Relative weight: 1
ReflectionResolution: 2.24→79.5 Å / Num. obs: 37400 / % possible obs: 98.6 % / Redundancy: 6.7 % / CC1/2: 0.99 / Rmerge(I) obs: 0.182 / Rpim(I) all: 0.083 / Rrim(I) all: 0.218 / Net I/σ(I): 6.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.6-2.726.31.87326560.3150.7862.03691
2.24-2.326.60.1066130.990.0430.11599.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.5.32data scaling
PHASERphasing
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 7SD5

7sd5


Resolution: 2.24→79.36 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 29.18 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.256 1988 5.32 %
Rwork0.2013 35412 -
obs0.2041 37400 98.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 131.46 Å2 / Biso mean: 56.8304 Å2 / Biso min: 28.07 Å2
Refinement stepCycle: final / Resolution: 2.24→79.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4852 0 42 109 5003
Biso mean--106.23 52.01 -
Num. residues----636
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.24-2.30.36451300.3155230191
2.3-2.360.32981420.2975254099
2.36-2.430.35861400.3011249299
2.43-2.510.34841440.2852553100
2.51-2.60.34371400.28412512100
2.6-2.710.32621440.26592536100
2.71-2.830.32641420.25112544100
2.83-2.980.29591430.23422542100
2.98-3.160.28331440.21752554100
3.16-3.410.25741420.2082253899
3.41-3.750.25481410.1903253199
3.75-4.290.23081460.16762580100
4.29-5.410.19761440.1522572100
5.41-8.920.21321460.1751261799

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