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- PDB-7dx4: The structure of FC08 Fab-hA.CE2-RBD complex -

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Basic information

Entry
Database: PDB / ID: 7dx4
TitleThe structure of FC08 Fab-hA.CE2-RBD complex
Components
  • Angiotensin-converting enzyme 2
  • Heavy chain of FC08 Fab
  • Light chain of FC08 Fab
  • Spike protein S1
KeywordsVIRAL PROTEIN / SARS-CoV-2 / Spike / neutralizing antibody / hACE2 / RBD
Function / homology
Function and homology information


positive regulation of amino acid transport / angiotensin-converting enzyme 2 / positive regulation of L-proline import across plasma membrane / angiotensin-mediated drinking behavior / Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases / regulation of systemic arterial blood pressure by renin-angiotensin / positive regulation of gap junction assembly / tryptophan transport / regulation of cardiac conduction / regulation of vasoconstriction ...positive regulation of amino acid transport / angiotensin-converting enzyme 2 / positive regulation of L-proline import across plasma membrane / angiotensin-mediated drinking behavior / Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases / regulation of systemic arterial blood pressure by renin-angiotensin / positive regulation of gap junction assembly / tryptophan transport / regulation of cardiac conduction / regulation of vasoconstriction / peptidyl-dipeptidase activity / maternal process involved in female pregnancy / Metabolism of Angiotensinogen to Angiotensins / carboxypeptidase activity / angiotensin maturation / receptor-mediated endocytosis of virus by host cell / Attachment and Entry / metallocarboxypeptidase activity / viral life cycle / positive regulation of cardiac muscle contraction / regulation of cytokine production / regulation of transmembrane transporter activity / blood vessel diameter maintenance / negative regulation of smooth muscle cell proliferation / brush border membrane / negative regulation of ERK1 and ERK2 cascade / metallopeptidase activity / positive regulation of reactive oxygen species metabolic process / endocytic vesicle membrane / regulation of cell population proliferation / virus receptor activity / regulation of inflammatory response / endopeptidase activity / Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / Potential therapeutics for SARS / 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 / cilium / symbiont-mediated suppression of host innate immune response / apical plasma membrane / receptor ligand activity / membrane raft / endocytosis involved in viral entry into host cell / endoplasmic reticulum lumen / symbiont 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 / cell surface / extracellular space / extracellular exosome / extracellular region / zinc ion binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Collectrin domain / Renal amino acid transporter / Collectrin-like domain profile. / Peptidase M2, peptidyl-dipeptidase A / Angiotensin-converting enzyme / Peptidase family M2 domain profile. / Neutral zinc metallopeptidases, zinc-binding region signature. / 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 ...Collectrin domain / Renal amino acid transporter / Collectrin-like domain profile. / Peptidase M2, peptidyl-dipeptidase A / Angiotensin-converting enzyme / Peptidase family M2 domain profile. / Neutral zinc metallopeptidases, zinc-binding region signature. / 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
Spike glycoprotein / Angiotensin-converting enzyme 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Severe acute respiratory syndrome coronavirus 2
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsCao, L. / Wang, X.
CitationJournal: Natl Sci Rev / Year: 2021
Title: A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2.
Authors: Li Zhang / Lei Cao / Xing-Su Gao / Bin-Yang Zheng / Yong-Qiang Deng / Jing-Xin Li / Rui Feng / Qian Bian / Xi-Ling Guo / Nan Wang / Hong-Ying Qiu / Lei Wang / Zhen Cui / Qing Ye / Geng Chen ...Authors: Li Zhang / Lei Cao / Xing-Su Gao / Bin-Yang Zheng / Yong-Qiang Deng / Jing-Xin Li / Rui Feng / Qian Bian / Xi-Ling Guo / Nan Wang / Hong-Ying Qiu / Lei Wang / Zhen Cui / Qing Ye / Geng Chen / Kui-Kui Lu / Yin Chen / Yu-Tao Chen / Hong-Xing Pan / Jiaping Yu / Wenrong Yao / Bao-Li Zhu / Jianping Chen / Yong Liu / Cheng-Feng Qin / Xiangxi Wang / Feng-Cai Zhu /
Abstract: Mutations and transient conformational movements of the receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable present immune escape routes for severe acute respiratory ...Mutations and transient conformational movements of the receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable present immune escape routes for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To mitigate viral escape, we developed a cocktail of neutralizing antibodies (NAbs) targeting epitopes located on different domains of spike (S) protein. Screening of a library of monoclonal antibodies generated from peripheral blood mononuclear cells of COVID-19 convalescent patients yielded potent NAbs, targeting the N-terminal domain (NTD) and RBD domain of S, effective at concentrations. Remarkably, a combination of RBD-targeting NAbs and NTD-binding NAbs, FC05, enhanced the neutralization potency in cell-based assays and an animal model. Results of competitive surface plasmon resonance assays and cryo-electron microscopy (cryo-EM) structures of antigen-binding fragments bound to S unveil determinants of immunogenicity. Combinations of immunogens, identified in the NTD and RBD of S, when immunized in rabbits and macaques, elicited potent protective immune responses against SARS-CoV-2. More importantly, two immunizations of this combination of NTD and RBD immunogens provided complete protection in macaques against a SARS-CoV-2 challenge, without observable antibody-dependent enhancement of infection. These results provide a proof of concept for neutralization-based immunogen design targeting SARS-CoV-2 NTD and RBD.
History
DepositionJan 18, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 21, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 23, 2022Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 6, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Angiotensin-converting enzyme 2
E: Spike protein S1
H: Heavy chain of FC08 Fab
L: Light chain of FC08 Fab
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,8559
Polymers115,7494
Non-polymers1,1065
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Angiotensin-converting enzyme 2 / Angiotensin-converting enzyme homolog / ACEH / Angiotensin-converting enzyme-related ...Angiotensin-converting enzyme homolog / ACEH / Angiotensin-converting enzyme-related carboxypeptidase / ACE-related carboxypeptidase / Metalloprotease MPROT15


Mass: 69153.664 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACE2, UNQ868/PRO1885 / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
References: UniProt: Q9BYF1, angiotensin-converting enzyme 2, Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases
#2: Protein Spike protein S1


Mass: 21776.381 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P0DTC2
#3: Antibody Heavy chain of FC08 Fab


Mass: 13346.900 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#4: Antibody Light chain of FC08 Fab


Mass: 11472.495 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#5: 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 / 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
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Severe acute respiratory syndrome coronavirus 2COMPLEX#1-#40RECOMBINANT
2Angiotensin-converting enzyme 2COMPLEX#11RECOMBINANT
3Spike protein S1COMPLEX#21RECOMBINANT
4FC08 FabCOMPLEX#3-#41RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Severe acute respiratory syndrome coronavirus 22697049
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
21Homo sapiens (human)9606HEK293
32Homo sapiens (human)9606HEK293
43Homo sapiens (human)9606HEK293
Details of virusEmpty: NO / Enveloped: YES / Isolate: OTHER / Type: PRION
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI TITAN
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.11.1_2575: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 87543 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0098468
ELECTRON MICROSCOPYf_angle_d0.94611521
ELECTRON MICROSCOPYf_dihedral_angle_d8.4456456
ELECTRON MICROSCOPYf_chiral_restr0.061225
ELECTRON MICROSCOPYf_plane_restr0.0071488

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