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- PDB-8d47: fp.006 Fab in complex with SARS-CoV-2 Fusion Peptide -

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Basic information

Entry
Database: PDB / ID: 8d47
Titlefp.006 Fab in complex with SARS-CoV-2 Fusion Peptide
Components
  • SARS-CoV-2 fusion peptide
  • fp.006 heavy chain
  • fp.006 light chain
KeywordsANTIVIRAL PROTEIN / antibody / fusion peptide / TMPRSS2 binding site / 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 / 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 ...Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / 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 / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / PHOSPHATE ION / Spike glycoprotein
Similarity search - Component
Biological speciesHomo sapiens (human)
Severe acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsAbernathy, M.E. / Barnes, C.O.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI)GT15335 United States
Citation
Journal: Sci Immunol / Year: 2023
Title: Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein.
Authors: Filippo Bianchini / Virginia Crivelli / Morgan E Abernathy / Concetta Guerra / Martin Palus / Jonathan Muri / Harold Marcotte / Antonio Piralla / Mattia Pedotti / Raoul De Gasparo / Luca ...Authors: Filippo Bianchini / Virginia Crivelli / Morgan E Abernathy / Concetta Guerra / Martin Palus / Jonathan Muri / Harold Marcotte / Antonio Piralla / Mattia Pedotti / Raoul De Gasparo / Luca Simonelli / Milos Matkovic / Chiara Toscano / Maira Biggiogero / Veronica Calvaruso / Pavel Svoboda / Tomás Cervantes Rincón / Tommaso Fava / Lucie Podešvová / Akanksha A Shanbhag / Andrea Celoria / Jacopo Sgrignani / Michal Stefanik / Vaclav Hönig / Veronika Pranclova / Tereza Michalcikova / Jan Prochazka / Giuditta Guerrini / Dora Mehn / Annalisa Ciabattini / Hassan Abolhassani / David Jarrossay / Mariagrazia Uguccioni / Donata Medaglini / Qiang Pan-Hammarström / Luigi Calzolai / Daniel Fernandez / Fausto Baldanti / Alessandra Franzetti-Pellanda / Christian Garzoni / Radislav Sedlacek / Daniel Ruzek / Luca Varani / Andrea Cavalli / Christopher O Barnes / Davide F Robbiani /
Abstract: Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies ...Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2' site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization, and, similar to fp.006 and hr2.016, protects mice expressing human angiotensin-converting enzyme 2 against infection when present as a bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae, including SARS-CoV-2 variants.
#1: Journal: bioRxiv / Year: 2022
Title: Human neutralizing antibodies to cold linear epitopes and to subdomain 1 of SARS-CoV-2.
Authors: Filippo Bianchini / Virginia Crivelli / Morgan E Abernathy / Concetta Guerra / Martin Palus / Jonathan Muri / Harold Marcotte / Antonio Piralla / Mattia Pedotti / Raoul De Gasparo / Luca ...Authors: Filippo Bianchini / Virginia Crivelli / Morgan E Abernathy / Concetta Guerra / Martin Palus / Jonathan Muri / Harold Marcotte / Antonio Piralla / Mattia Pedotti / Raoul De Gasparo / Luca Simonelli / Milos Matkovic / Chiara Toscano / Maira Biggiogero / Veronica Calvaruso / Pavel Svoboda / Tomás Cervantes Rincón / Tommaso Fava / Lucie Podešvová / Akanksha A Shanbhag / Andrea Celoria / Jacopo Sgrignani / Michal Stefanik / Vaclav Hönig / Veronika Pranclova / Tereza Michalcikova / Jan Prochazka / Giuditta Guerrini / Dora Mehn / Annalisa Ciabattini / Hassan Abolhassani / David Jarrossay / Mariagrazia Uguccioni / Donata Medaglini / Qiang Pan-Hammarström / Luigi Calzolai / Daniel Fernandez / Fausto Baldanti / Alessandra Franzetti-Pellanda / Christian Garzoni / Radislav Sedlacek / Daniel Ruzek / Luca Varani / Andrea Cavalli / Christopher O Barnes / Davide F Robbiani /
Abstract: Emergence of SARS-CoV-2 variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution ...Emergence of SARS-CoV-2 variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four , including the nine human coronaviruses, through recognition of a conserved motif that includes the S2' site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization and, like fp.006 and hr2.016, protects mice when present as bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with , including SARS-CoV-2 variants.
ONE SENTENCE SUMMARY: Broadly cross-reactive antibodies that protect from SARS-CoV-2 variants are revealed by virus coldspot-driven discovery.
History
DepositionJun 1, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 21, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 16, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Revision 1.2Oct 25, 2023Group: Refinement description / Category: pdbx_initial_refinement_model
Revision 1.3Oct 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

Downloads & links

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Assembly

Deposited unit
L: fp.006 light chain
A: fp.006 light chain
H: fp.006 heavy chain
B: fp.006 heavy chain
C: SARS-CoV-2 fusion peptide
D: SARS-CoV-2 fusion peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)104,08814
Polymers103,3276
Non-polymers7608
Water13,547752
1
L: fp.006 light chain
H: fp.006 heavy chain
C: SARS-CoV-2 fusion peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,8325
Polymers51,6643
Non-polymers1682
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5350 Å2
ΔGint-25 kcal/mol
Surface area19990 Å2
MethodPISA
2
A: fp.006 light chain
B: fp.006 heavy chain
D: SARS-CoV-2 fusion peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,2569
Polymers51,6643
Non-polymers5926
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5990 Å2
ΔGint-49 kcal/mol
Surface area20000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.017, 73.076, 90.117
Angle α, β, γ (deg.)90.000, 109.010, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein/peptide , 1 types, 2 molecules CD

#3: Protein/peptide SARS-CoV-2 fusion peptide


Mass: 2267.600 Da / Num. of mol.: 2 / Source method: obtained synthetically
Source: (synth.) Severe acute respiratory syndrome coronavirus 2
References: UniProt: P0DTC2

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Antibody , 2 types, 4 molecules LAHB

#1: Antibody fp.006 light chain


Mass: 23236.789 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293F / Production host: Homo sapiens (human)
#2: Antibody fp.006 heavy chain


Mass: 26159.256 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293F / Production host: Homo sapiens (human)

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Non-polymers , 4 types, 760 molecules

#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 752 / 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: 2.71 Å3/Da / Density % sol: 54.65 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 4.8
Details: 0.2 M Potassium phosphate monobasic, 20% w/v Polyethylene glycol 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-1 / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 1, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2→37.9 Å / Num. obs: 73148 / % possible obs: 97.9 % / Redundancy: 3 % / Biso Wilson estimate: 26.71 Å2 / CC1/2: 0.988 / Rmerge(I) obs: 0.117 / Net I/σ(I): 6.1
Reflection shellResolution: 2→2.04 Å / Redundancy: 3 % / Rmerge(I) obs: 0.996 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 4545 / CC1/2: 0.372 / % possible all: 98.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GXU, 6FG1

4gxu

6fg1


Resolution: 2→37.89 Å / SU ML: 0.2588 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 23.8159
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2378 3634 4.97 %
Rwork0.1836 69425 -
obs0.1862 73059 97.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 31.33 Å2
Refinement stepCycle: LAST / Resolution: 2→37.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6902 0 45 752 7699
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00697119
X-RAY DIFFRACTIONf_angle_d0.83969667
X-RAY DIFFRACTIONf_chiral_restr0.05391081
X-RAY DIFFRACTIONf_plane_restr0.00661241
X-RAY DIFFRACTIONf_dihedral_angle_d7.0642999
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.030.34271430.27782636X-RAY DIFFRACTION98.37
2.03-2.050.29341330.26772652X-RAY DIFFRACTION98.69
2.05-2.080.32781430.26252673X-RAY DIFFRACTION98.22
2.08-2.110.28991490.2522686X-RAY DIFFRACTION98.3
2.11-2.150.28371470.22972691X-RAY DIFFRACTION98.34
2.15-2.180.28691760.22562622X-RAY DIFFRACTION98.56
2.18-2.220.28031300.22082650X-RAY DIFFRACTION97.37
2.22-2.260.28711670.21122631X-RAY DIFFRACTION97.42
2.26-2.30.2821390.21382645X-RAY DIFFRACTION97.82
2.3-2.350.26531040.21422692X-RAY DIFFRACTION97.18
2.35-2.40.30351540.21552610X-RAY DIFFRACTION97.02
2.4-2.460.26191410.20682657X-RAY DIFFRACTION96.78
2.46-2.520.26311450.20412570X-RAY DIFFRACTION93.72
2.52-2.590.25231510.19362649X-RAY DIFFRACTION98.49
2.59-2.660.24931120.18752752X-RAY DIFFRACTION99.44
2.66-2.750.28881350.19372700X-RAY DIFFRACTION99.37
2.75-2.850.25311450.18762709X-RAY DIFFRACTION99.41
2.85-2.960.27991520.1952709X-RAY DIFFRACTION98.89
2.96-3.10.24761440.19712700X-RAY DIFFRACTION98.78
3.1-3.260.23391490.19322629X-RAY DIFFRACTION96.83
3.26-3.460.21021400.17042666X-RAY DIFFRACTION96.29
3.46-3.730.21331320.1662600X-RAY DIFFRACTION94.27
3.73-4.110.18891450.15892725X-RAY DIFFRACTION99.38
4.11-4.70.17431080.12372754X-RAY DIFFRACTION99.13
4.7-5.920.1771390.14562723X-RAY DIFFRACTION97.75
5.92-37.890.21021110.17072694X-RAY DIFFRACTION93.66

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