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- PDB-9dgo: Designed miniproteins potently inhibit and protect against MERS-C... -

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Basic information

Entry
Database: PDB / ID: 9dgo
TitleDesigned miniproteins potently inhibit and protect against MERS-CoV. Crystal structure of MERS-CoV S RBD in complex with miniprotein cb3
Components
  • Designed miniprotein cb_3
  • Spike glycoprotein
KeywordsVIRAL PROTEIN / MERS-CoV / miniproteins / neutralization / fusion / cryo-EM / biolayer interferometry / MERS-CoV strains / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID
Function / homology
Function and homology information


host cell endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated virion attachment to host cell / 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 / host cell plasma membrane / virion membrane / membrane
Similarity search - Function
Spike (S) protein S1 subunit, receptor-binding domain, MERS-CoV / Spike (S) protein S1 subunit, N-terminal domain, MERS-CoV-like / Spike glycoprotein S2, coronavirus, C-terminal / Coronavirus spike glycoprotein S2, intravirion / 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 (S) protein S1 subunit, receptor-binding domain, MERS-CoV / Spike (S) protein S1 subunit, N-terminal domain, MERS-CoV-like / Spike glycoprotein S2, coronavirus, C-terminal / Coronavirus spike glycoprotein S2, intravirion / 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 speciesMiddle East respiratory syndrome-related coronavirus
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsTortorici, M.A. / Veesler, D. / Seattle Structural Genomics Center for Infectious Disease (SSGCID)
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI158186 United States
CitationJournal: Cell Rep / Year: 2025
Title: Designed miniproteins potently inhibit and protect against MERS-CoV.
Authors: Robert J Ragotte / M Alejandra Tortorici / Nicholas J Catanzaro / Amin Addetia / Brian Coventry / Heather M Froggatt / Jimin Lee / Cameron Stewart / Jack T Brown / Inna Goreshnik / Jeremiah ...Authors: Robert J Ragotte / M Alejandra Tortorici / Nicholas J Catanzaro / Amin Addetia / Brian Coventry / Heather M Froggatt / Jimin Lee / Cameron Stewart / Jack T Brown / Inna Goreshnik / Jeremiah N Sims / Lukas F Milles / Basile I M Wicky / Matthias Glögl / Stacey Gerben / Alex Kang / Asim K Bera / William Sharkey / Alexandra Schäfer / Jack R Harkema / Ralph S Baric / David Baker / David Veesler /
Abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic pathogen with a 36% case-fatality rate in humans. No vaccines or specific therapeutics are currently approved for use in humans ...Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic pathogen with a 36% case-fatality rate in humans. No vaccines or specific therapeutics are currently approved for use in humans or the camel host reservoir. Here, we computationally designed monomeric and homo-oligomeric miniproteins that bind with high affinity to the MERS-CoV spike (S) glycoprotein, the main target of neutralizing antibodies and vaccine development. We show that these miniproteins broadly neutralize a panel of MERS-CoV S variants, spanning the known antigenic diversity of this pathogen, by targeting a conserved site in the receptor-binding domain (RBD). The miniproteins directly compete with binding of the dipeptidylpeptidase 4 (DPP4) receptor to MERS-CoV S, thereby blocking viral attachment to the host entry receptor and subsequent membrane fusion. Intranasal administration of a lead miniprotein provides prophylactic protection against stringent MERS-CoV challenge in mice, motivating its future clinical development as a next-generation countermeasure against this virus with pandemic potential.
History
DepositionSep 3, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 18, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Spike glycoprotein
B: Spike glycoprotein
C: Designed miniprotein cb_3
D: Designed miniprotein cb_3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,6218
Polymers70,1674
Non-polymers1,4534
Water5,513306
1
A: Spike glycoprotein
D: Designed miniprotein cb_3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7294
Polymers35,0842
Non-polymers6462
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2360 Å2
ΔGint4 kcal/mol
Surface area12570 Å2
MethodPISA
2
B: Spike glycoprotein
C: Designed miniprotein cb_3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8914
Polymers35,0842
Non-polymers8082
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2310 Å2
ΔGint5 kcal/mol
Surface area13650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.619, 76.291, 136.235
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 4 molecules ABCD

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


Mass: 28045.938 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Middle East respiratory syndrome-related coronavirus
Production host: Homo sapiens (human) / References: UniProt: A0A0U2GPS7
#2: Protein Designed miniprotein cb_3


Mass: 7037.672 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)

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Sugars , 3 types, 4 molecules

#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#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.: 2 / 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

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Non-polymers , 1 types, 306 molecules

#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 306 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.49 Å3/Da / Density % sol: 50.54 %
Crystal growTemperature: 296 K / Method: vapor diffusion, hanging drop
Details: 0.16 M MgCl2, 0.08 M Tris-HCl pH 8.5, 24%(w/v) PEG4000, 20% (v/v) glycerol

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 12, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→31.55 Å / Num. obs: 55567 / % possible obs: 100 % / Redundancy: 2 % / CC1/2: 0.99 / Rmerge(I) obs: 0.023 / Net I/σ(I): 14.7
Reflection shellResolution: 1.88→1.95 Å / Num. unique obs: 55567 / CC1/2: 0.023

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Processing

Software
NameVersionClassification
PHENIX(1.21.2_5419: ???)refinement
XDSdata reduction
XDSdata scaling
PHENIX(1.21_5207-000)phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→31.55 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.62 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2189 2758 4.96 %
Rwork0.1899 --
obs0.1913 55566 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.85→31.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4049 0 95 306 4450
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007
X-RAY DIFFRACTIONf_angle_d0.843
X-RAY DIFFRACTIONf_dihedral_angle_d11.8571621
X-RAY DIFFRACTIONf_chiral_restr0.054691
X-RAY DIFFRACTIONf_plane_restr0.007753
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.880.3711320.29252617X-RAY DIFFRACTION100
1.88-1.920.28021540.26232572X-RAY DIFFRACTION100
1.92-1.950.29831530.23312611X-RAY DIFFRACTION100
1.95-1.990.25251290.21662576X-RAY DIFFRACTION100
1.99-2.040.25971260.20552620X-RAY DIFFRACTION100
2.04-2.080.24411400.19622593X-RAY DIFFRACTION100
2.08-2.140.22481130.18972663X-RAY DIFFRACTION100
2.14-2.190.25391510.18942578X-RAY DIFFRACTION100
2.19-2.260.25821360.19712620X-RAY DIFFRACTION100
2.26-2.330.22151440.19272616X-RAY DIFFRACTION100
2.33-2.410.22881400.19522602X-RAY DIFFRACTION100
2.41-2.510.21741180.20042644X-RAY DIFFRACTION100
2.51-2.620.22771560.19932632X-RAY DIFFRACTION100
2.62-2.760.21151230.19732638X-RAY DIFFRACTION100
2.76-2.940.27051690.20222635X-RAY DIFFRACTION100
2.94-3.160.23491300.18922660X-RAY DIFFRACTION100
3.16-3.480.18961250.18282677X-RAY DIFFRACTION100
3.48-3.980.19891420.1642677X-RAY DIFFRACTION100
3.98-5.010.18881450.15942714X-RAY DIFFRACTION100
5.02-5.60.20411320.22863X-RAY DIFFRACTION100

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