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- PDB-7r6x: SARS-CoV-2 spike receptor-binding domain (RBD) in complex with S2... -

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Basic information

Entry
Database: PDB / ID: 7r6x
TitleSARS-CoV-2 spike receptor-binding domain (RBD) in complex with S2E12 Fab, S309 Fab, and S304 Fab
Components
  • (Monoclonal antibody S2E12 Fab ...) x 2
  • (Monoclonal antibody S304 Fab ...) x 2
  • (Monoclonal antibody S309 Fab ...) x 2
  • Spike protein S1
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / COVID-19 / SARS-CoV-2 / neutralizing monoclonal antibody / VIRAL PROTEIN-IMMUNE SYSTEM complex
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 speciesHomo sapiens (human)
Severe acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsSnell, G. / Czudnochowski, N. / Croll, T.I. / Nix, J.C. / Corti, D. / Cameroni, E. / Pinto, D. / Beltramello, M.
Citation
Journal: Nature / Year: 2021
Title: SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape.
Authors: Tyler N Starr / Nadine Czudnochowski / Zhuoming Liu / Fabrizia Zatta / Young-Jun Park / Amin Addetia / Dora Pinto / Martina Beltramello / Patrick Hernandez / Allison J Greaney / Roberta ...Authors: Tyler N Starr / Nadine Czudnochowski / Zhuoming Liu / Fabrizia Zatta / Young-Jun Park / Amin Addetia / Dora Pinto / Martina Beltramello / Patrick Hernandez / Allison J Greaney / Roberta Marzi / William G Glass / Ivy Zhang / Adam S Dingens / John E Bowen / M Alejandra Tortorici / Alexandra C Walls / Jason A Wojcechowskyj / Anna De Marco / Laura E Rosen / Jiayi Zhou / Martin Montiel-Ruiz / Hannah Kaiser / Josh R Dillen / Heather Tucker / Jessica Bassi / Chiara Silacci-Fregni / Michael P Housley / Julia di Iulio / Gloria Lombardo / Maria Agostini / Nicole Sprugasci / Katja Culap / Stefano Jaconi / Marcel Meury / Exequiel Dellota / Rana Abdelnabi / Shi-Yan Caroline Foo / Elisabetta Cameroni / Spencer Stumpf / Tristan I Croll / Jay C Nix / Colin Havenar-Daughton / Luca Piccoli / Fabio Benigni / Johan Neyts / Amalio Telenti / Florian A Lempp / Matteo S Pizzuto / John D Chodera / Christy M Hebner / Herbert W Virgin / Sean P J Whelan / David Veesler / Davide Corti / Jesse D Bloom / Gyorgy Snell /
Abstract: An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape, have activity against diverse sarbecoviruses, and be highly protective through viral neutralization and effector functions. ...An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape, have activity against diverse sarbecoviruses, and be highly protective through viral neutralization and effector functions. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E12) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.
#1: Journal: To Be Published
Title: SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape
Authors: Starr, T.N. / Czudnochowski, N. / Liu, Z. / Zatta, F. / Park, Y.J. / Pinto, D. / Beltramello, M. / Hernandez, P. / Cameroni, E. / Croll, T.I. / Nix, J.C. / Chodera, J.D. / Whelan, S.P.J. / ...Authors: Starr, T.N. / Czudnochowski, N. / Liu, Z. / Zatta, F. / Park, Y.J. / Pinto, D. / Beltramello, M. / Hernandez, P. / Cameroni, E. / Croll, T.I. / Nix, J.C. / Chodera, J.D. / Whelan, S.P.J. / Virgin, H.W. / Corti, D. / Veesler, D. / Bloom, J.D. / Snell, G.
History
DepositionJun 23, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 21, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 28, 2021Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 15, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 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
L: Monoclonal antibody S304 Fab light chain
H: Monoclonal antibody S304 Fab heavy chain
R: Spike protein S1
B: Monoclonal antibody S309 Fab light chain
A: Monoclonal antibody S309 Fab heavy chain
D: Monoclonal antibody S2E12 Fab light chain
C: Monoclonal antibody S2E12 Fab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)167,17510
Polymers166,8837
Non-polymers2923
Water543
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)245.870, 245.870, 237.310
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number98
Space group name H-MI4122

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Components

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Antibody , 6 types, 6 molecules LHBADC

#1: Antibody Monoclonal antibody S304 Fab light chain


Mass: 23369.947 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293.sus / Production host: Homo sapiens (human)
#2: Antibody Monoclonal antibody S304 Fab heavy chain


Mass: 23729.389 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293.sus / Production host: Homo sapiens (human)
#4: Antibody Monoclonal antibody S309 Fab light chain


Mass: 23204.697 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293.sus / Production host: Homo sapiens (human)
#5: Antibody Monoclonal antibody S309 Fab heavy chain


Mass: 24573.471 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293.sus / Production host: Homo sapiens (human)
#6: Antibody Monoclonal antibody S2E12 Fab light chain


Mass: 23546.127 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#7: Antibody Monoclonal antibody S2E12 Fab heavy chain


Mass: 24016.900 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)

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Protein / Sugars , 2 types, 2 molecules R

#3: Protein Spike protein S1


Mass: 24442.332 Da / Num. of mol.: 1 / Fragment: receptor-binding domain (UNP residues 328-531)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: S, 2 / Production host: Homo sapiens (human) / References: UniProt: P0DTC2
#8: 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 / N-Acetylglucosamine


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

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Non-polymers , 2 types, 5 molecules

#9: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 5.37 Å3/Da / Density % sol: 77.11 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: Crystal 1: 0.09 M phosphate/citrate, pH 5.5, 27% v/v PEG Smear Low, 4% v/v polypropylene glycol 400, 0.02 M imidazole, pH 7, Crystal 2: 0.09 M phosphate/citrate, pH 5.5, 27% v/v PEG Smear ...Details: Crystal 1: 0.09 M phosphate/citrate, pH 5.5, 27% v/v PEG Smear Low, 4% v/v polypropylene glycol 400, 0.02 M imidazole, pH 7, Crystal 2: 0.09 M phosphate/citrate, pH 5.5, 27% v/v PEG Smear Low, 0.01 M potassium/sodium phosphate, pH 7, 1% v/v PPGBA 230, 1.5% v/v PPGBA 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1.00003 Å
DetectorType: RDI CMOS_8M / Detector: CMOS / Date: Oct 4, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2.93→49 Å / Num. obs: 77621 / % possible obs: 100 % / Redundancy: 28.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.295 / Rpim(I) all: 0.056 / Rrim(I) all: 0.3 / Net I/σ(I): 13.3 / Num. measured all: 2242103
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
2.93-2.9927.27.86812372845510.3811.5318.0160.5100
14.65-4924.80.048171296920.9980.010.04965.397.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
Aimlessdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 7JX3 and 7K3Q

7jx3

7k3q


Resolution: 2.95→40 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.906 / SU B: 33.532 / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.357 / ESU R Free: 0.282 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2624 3806 5.1 %RANDOM
Rwork0.2323 ---
obs0.2338 71532 98.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 240.68 Å2 / Biso mean: 116.456 Å2 / Biso min: 58.09 Å2
Baniso -1Baniso -2Baniso -3
1--0.38 Å2-0 Å20 Å2
2---0.38 Å20 Å2
3---0.76 Å2
Refinement stepCycle: final / Resolution: 2.95→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9101 0 16 3 9120
Biso mean--122.78 65.9 -
Num. residues----1189
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0129346
X-RAY DIFFRACTIONr_angle_refined_deg0.9361.64212720
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.99951176
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.19322.315432
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.945151434
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1651546
X-RAY DIFFRACTIONr_chiral_restr0.0730.21225
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.027158
LS refinement shellResolution: 2.95→3.026 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.409 248 -
Rwork0.408 4622 -
all-4870 -
obs--87.65 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.9363-0.8513-0.20517.57720.33940.86170.17760.09650.7786-0.2743-0.30761.1937-0.875-0.39830.130.8910.4008-0.15470.5325-0.02410.9433-25.1245.015-12.844
22.91820.31790.09356.3893-0.33722.22130.0128-0.01580.9698-0.3534-0.00940.4638-1.2557-0.3011-0.00330.77880.1411-0.07060.16840.01890.6673-6.59948.633-9.965
33.7988-0.6931-1.19043.7419-1.1194.57370.02850.7605-0.0079-0.4293-0.2402-0.0619-0.16680.02420.21170.08280.0167-0.04940.2438-0.03970.47831.16615.709-32.104
46.2769-0.2060.16610.7548-0.07861.0680.0269-0.06750.3083-0.04480.0364-0.0349-0.11540.1886-0.06330.0262-0.01630.07860.2486-0.01560.498452.11717.355-21.787
55.74630.4580.37351.12020.00610.81860.1392-0.3025-0.00190.131-0.0901-0.06960.04890.3694-0.04920.03350.01850.06680.23840.0270.433543.664.984-11.724
61.77732.3539-1.27073.4233-1.63080.9736-0.80750.82040.1672-1.60690.66720.66520.7117-0.50810.14032.11270.1967-0.46662.3949-0.10610.9764-11.13414.335-76.799
71.10760.7111-0.17746.1743-1.13353.91170.26110.96650.442-0.9814-0.0575-0.1691-0.46680.4534-0.20361.1430.0772-0.14351.87090.30470.9208-2.69428.499-67.192
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1L1 - 180
2X-RAY DIFFRACTION2H2 - 215
3X-RAY DIFFRACTION3R330 - 528
4X-RAY DIFFRACTION4B1 - 213
5X-RAY DIFFRACTION5A1 - 229
6X-RAY DIFFRACTION6D1 - 103
7X-RAY DIFFRACTION7C1 - 122

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