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- PDB-8ydw: Crystal structure of the receptor binding domain of SARS-CoV-2 Om... -

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Basic information

Entry
Database: PDB / ID: 8ydw
TitleCrystal structure of the receptor binding domain of SARS-CoV-2 Omicron XBB.1.5 variant spike protein in complex with CeSPIACE
Components
  • SARS-CoV-2 inhibiting peptide CeSPIACE
  • Spike protein S1
KeywordsVIRAL PROTEIN/INHIBITOR / RBD / VIRAL PROTEIN-INHIBITOR COMPLEX
Function / homology
Function and homology information


symbiont-mediated disruption of host tissue / Maturation of spike protein / 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 / membrane fusion ...symbiont-mediated disruption of host tissue / Maturation of spike protein / 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 / membrane fusion / Attachment and Entry / entry receptor-mediated virion attachment to host cell / 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 / endocytosis involved in viral entry into host cell / receptor ligand activity / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / symbiont entry into host cell / virion attachment to host cell / host cell plasma membrane / SARS-CoV-2 activates/modulates innate and adaptive immune responses / 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, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal ...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, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S2 superfamily, coronavirus / 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, coronavirus / Coronavirus spike glycoprotein S2
Similarity search - Domain/homology
Biological speciesSevere acute respiratory syndrome coronavirus 2
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsNakamura, S. / Numoto, N. / Fujiyoshi, Y.
Funding support Japan, 2items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)JP21fk0108462, JP21fk0108585, JP21ae0121028, JP18ae0101046 Japan
Japan Society for the Promotion of Science (JSPS)20H00451 Japan
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Structure-guided engineering of a mutation-tolerant inhibitor peptide against variable SARS-CoV-2 spikes.
Authors: Shun Nakamura / Yukihiro Tanimura / Risa Nomura / Hiroshi Suzuki / Kouki Nishikawa / Akiko Kamegawa / Nobutaka Numoto / Atsushi Tanaka / Shigeru Kawabata / Shoichi Sakaguchi / Akino Emi / ...Authors: Shun Nakamura / Yukihiro Tanimura / Risa Nomura / Hiroshi Suzuki / Kouki Nishikawa / Akiko Kamegawa / Nobutaka Numoto / Atsushi Tanaka / Shigeru Kawabata / Shoichi Sakaguchi / Akino Emi / Youichi Suzuki / Yoshinori Fujiyoshi /
Abstract: Pathogen mutations present an inevitable and challenging problem for therapeutics and the development of mutation-tolerant anti-infective drugs to strengthen global health and combat evolving ...Pathogen mutations present an inevitable and challenging problem for therapeutics and the development of mutation-tolerant anti-infective drugs to strengthen global health and combat evolving pathogens is urgently needed. While spike proteins on viral surfaces are attractive targets for preventing viral entry, they mutate frequently, making it difficult to develop effective therapeutics. Here, we used a structure-guided strategy to engineer an inhibitor peptide against the SARS-CoV-2 spike, called CeSPIACE, with mutation-tolerant and potent binding ability against all variants to enhance affinity for the invariant architecture of the receptor-binding domain (RBD). High-resolution structures of the peptide complexed with mutant RBDs revealed a mechanism of mutation-tolerant inhibition. CeSPIACE bound major mutant RBDs with picomolar affinity and inhibited infection by SARS-CoV-2 variants in VeroE6/TMPRSS2 cells (IC 4 pM to 13 nM) and demonstrated potent in vivo efficacy by inhalation administration in hamsters. Mutagenesis analyses to address mutation risks confirmed tolerance against existing and/or potential future mutations of the RBD. Our strategy of engineering mutation-tolerant inhibitors may be applicable to other infectious diseases.
History
DepositionFeb 21, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 15, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: SARS-CoV-2 inhibiting peptide CeSPIACE
B: Spike protein S1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,0414
Polymers30,9262
Non-polymers1152
Water1,31573
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2320 Å2
ΔGint-14 kcal/mol
Surface area11830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.760, 74.760, 100.070
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein/peptide SARS-CoV-2 inhibiting peptide CeSPIACE


Mass: 4721.475 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#2: Protein Spike protein S1


Mass: 26204.250 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: S, 2 / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: P0DTC2
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 73 / Source method: isolated from a natural source / Formula: H2O
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: 2.61 Å3/Da / Density % sol: 52.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M CHES (pH 9.5), 20% PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 14, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.72→50 Å / Num. obs: 34940 / % possible obs: 99.9 % / Redundancy: 13 % / CC1/2: 0.999 / Net I/σ(I): 16.09
Reflection shellResolution: 1.72→1.82 Å / Num. unique obs: 5379 / CC1/2: 0.702

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Processing

Software
NameVersionClassification
REFMAC5.8.0411refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→39.622 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.943 / Cross valid method: FREE R-VALUE / ESU R: 0.174 / ESU R Free: 0.157
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2538 1111 4.963 %
Rwork0.223 21276 -
all0.225 --
obs-22387 99.893 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 65.885 Å2
Baniso -1Baniso -2Baniso -3
1-2.838 Å21.419 Å20 Å2
2--2.838 Å2-0 Å2
3----9.206 Å2
Refinement stepCycle: LAST / Resolution: 2→39.622 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1889 0 7 73 1969
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0121950
X-RAY DIFFRACTIONr_bond_other_d0.0020.0161772
X-RAY DIFFRACTIONr_angle_refined_deg1.3461.6482648
X-RAY DIFFRACTIONr_angle_other_deg0.7691.5694078
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2845234
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.672511
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.12710305
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.7761095
X-RAY DIFFRACTIONr_chiral_restr0.0640.2277
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022294
X-RAY DIFFRACTIONr_gen_planes_other0.0090.02486
X-RAY DIFFRACTIONr_nbd_refined0.2310.2392
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2160.21740
X-RAY DIFFRACTIONr_nbtor_refined0.1930.2974
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0860.21035
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1490.284
X-RAY DIFFRACTIONr_metal_ion_refined0.0410.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.0610.26
X-RAY DIFFRACTIONr_nbd_other0.1650.252
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1230.23
X-RAY DIFFRACTIONr_mcbond_it5.7346.622942
X-RAY DIFFRACTIONr_mcbond_other5.7326.622942
X-RAY DIFFRACTIONr_mcangle_it7.81311.8641174
X-RAY DIFFRACTIONr_mcangle_other7.80911.8661175
X-RAY DIFFRACTIONr_scbond_it6.0997.0191008
X-RAY DIFFRACTIONr_scbond_other6.0827.0151007
X-RAY DIFFRACTIONr_scangle_it8.60912.7091474
X-RAY DIFFRACTIONr_scangle_other8.60612.711475
X-RAY DIFFRACTIONr_lrange_it10.85863.6792222
X-RAY DIFFRACTIONr_lrange_other10.84863.6982217
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2-2.0520.308800.40715430.40216230.8010.8221000.369
2.052-2.1080.319770.38914920.38515730.8250.84499.74570.355
2.108-2.1690.385800.34614770.34815580.8650.88599.93580.305
2.169-2.2350.375720.3314190.33314920.9150.91399.9330.299
2.235-2.3080.269720.27413920.27414640.9220.941000.246
2.308-2.3890.298700.25413360.25614070.9290.9599.92890.229
2.389-2.4790.291700.25313030.25513740.9440.95599.92720.229
2.479-2.580.267620.23512390.23613050.9470.96299.69350.213
2.58-2.6940.258630.22111960.22312600.9590.96499.92060.207
2.694-2.8250.333620.23111500.23512120.9320.9631000.22
2.825-2.9770.284600.24611000.24811600.9550.961000.233
2.977-3.1560.289560.24610400.24910960.9450.9581000.244
3.156-3.3730.322500.2469690.2510190.9260.9631000.236
3.373-3.6410.232490.239260.239750.9570.9691000.233
3.641-3.9850.33420.2098460.2148920.9350.97499.55160.222
3.985-4.450.196410.1817750.1828170.9720.97999.87760.206
4.45-5.1270.197330.1756960.1767300.9720.98399.8630.204
5.127-6.2530.182320.1975980.1966300.980.981000.239
6.253-8.7350.221240.1844680.1864920.9760.9791000.224
8.735-39.6220.191160.1763030.1773210.9750.97799.37690.225

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