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

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Basic information

Entry
Database: PDB / ID: 7ttx
TitleCrystal structure of potent neutralizing antibody 10-40 in complex with Sarbecovirus bat RaTG13 receptor-binding domain
Components
  • 1040 heavy chain
  • 1040 light chain
  • Spike glycoprotein
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / COVID-19 / SarbecoVirus / RaTG13 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


endocytosis involved in viral entry into host cell / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated virion attachment to 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 / 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 (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 speciesBat coronavirus RaTG13
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 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 2, 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 1.3Aug 10, 2022Group: Structure summary / Category: struct / struct_keywords / Item: _struct.title / _struct_keywords.text
Revision 1.4Oct 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)75,0294
Polymers74,8073
Non-polymers2211
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5570 Å2
ΔGint-16 kcal/mol
Surface area28250 Å2
Unit cell
Length a, b, c (Å)74.174, 76.816, 117.626
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Spike glycoprotein / S glycoprotein / E2 / Peplomer protein


Mass: 26209.514 Da / Num. of mol.: 1 / Fragment: receptor-binding domain (UNP residues 319-541)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bat coronavirus RaTG13 / Production host: Homo sapiens (human) / References: UniProt: A0A6B9WHD3
#2: Antibody 1040 heavy chain


Mass: 25340.330 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.: 1 / 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
Has ligand of interestN

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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: 2.24 Å3/Da / Density % sol: 45.08 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 1 M lithium chloride, 30% w/v PEG6000, 0.1 M sodium acetate

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Data collection

DiffractionMean temperature: 110 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97911 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97911 Å / Relative weight: 1
ReflectionResolution: 2.67→117.63 Å / Num. obs: 19519 / % possible obs: 98.9 % / Redundancy: 12.8 % / CC1/2: 0.997 / Rmerge(I) obs: 0.173 / Rpim(I) all: 0.05 / Rrim(I) all: 0.18 / Net I/σ(I): 8.8 / Num. measured all: 249834
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.67-2.811.72.2592844924330.4810.6692.3610.994.5
8.85-117.6311.10.08767996140.9960.0260.09125.198.2

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Processing

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

7sd5


Resolution: 2.8→64.32 Å / SU ML: 0.54 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 37.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3211 849 4.99 %
Rwork0.2222 16159 -
obs0.2269 17008 99.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 160.43 Å2 / Biso mean: 81.0103 Å2 / Biso min: 36.89 Å2
Refinement stepCycle: final / Resolution: 2.8→64.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4867 0 14 0 4881
Biso mean--126.73 --
Num. residues----635
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8-2.980.4581350.387926632798100
2.98-3.210.38181390.30092628276799
3.21-3.530.38661410.262659280099
3.53-4.040.32221370.22382683282099
4.04-5.090.30041520.19882687283999
5.09-64.320.28361450.19092839298499

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