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- EMDB-46960: Designed miniproteins potently inhibit and protect against MERS-C... -

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Basic information

Entry
Database: EMDB / ID: EMD-46960
TitleDesigned miniproteins potently inhibit and protect against MERS-CoV. MERS-CoV S in complex with miniprotein cb3_GGGSGGGS_SB175, linker 7 (Local refinement of two RBDs and 2 miniproteins)
Map dataMain map
Sample
  • Complex: MERS-CoV S in complex with miniprotein cb3_GGGSGGGS_SB175, linker 7 (Local refinement of two RBDs and 2 miniproteins)
    • Protein or peptide: Spike protein
    • Protein or peptide: Miniprotein cb3_GGGSGGGS_SB175
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsCoronavirus / betacoronavirus / MERS-CoV / single particle cryo-EM / neutralization assays / binding assays / miniproteins inhibitors / fusion assays / in vivo protection / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / VIRAL PROTEIN
Biological speciesMiddle East respiratory syndrome-related coronavirus / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsTortorici MA / Veesler D / Seattle Structural Genomics Center for Infectious Disease (SSGCID)
Funding support United States, 1 items
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 9, 2024-
Header (metadata) releaseOct 15, 2025-
Map releaseOct 15, 2025-
UpdateFeb 25, 2026-
Current statusFeb 25, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46960.png

Downloads & links

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Map

FileDownload / File: emd_46960.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMain map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 512 pix.
= 512. Å		1 Å/pix.
x 512 pix.
= 512. Å		1 Å/pix.
x 512 pix.
= 512. Å

Surface

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Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.519
Minimum - Maximum-2.5023959 - 4.2420897
Average (Standard dev.)-0.00013479989 (±0.041203517)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 512.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Unsharpened map

Fileemd_46960_additional_1.map
AnnotationUnsharpened map
Projections & Slices
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Half map: Half map A

Fileemd_46960_half_map_1.map
AnnotationHalf map A
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_46960_half_map_2.map
AnnotationHalf map B
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : MERS-CoV S in complex with miniprotein cb3_GGGSGGGS_SB175, linker...

EntireName: MERS-CoV S in complex with miniprotein cb3_GGGSGGGS_SB175, linker 7 (Local refinement of two RBDs and 2 miniproteins)
Components
  • Complex: MERS-CoV S in complex with miniprotein cb3_GGGSGGGS_SB175, linker 7 (Local refinement of two RBDs and 2 miniproteins)
    • Protein or peptide: Spike protein
    • Protein or peptide: Miniprotein cb3_GGGSGGGS_SB175
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: MERS-CoV S in complex with miniprotein cb3_GGGSGGGS_SB175, linker...

SupramoleculeName: MERS-CoV S in complex with miniprotein cb3_GGGSGGGS_SB175, linker 7 (Local refinement of two RBDs and 2 miniproteins)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Middle East respiratory syndrome-related coronavirus

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Macromolecule #1: Spike protein

MacromoleculeName: Spike protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Middle East respiratory syndrome-related coronavirus
Molecular weightTheoretical: 150.005953 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGILPSPGMP ALLSLVSLLS VLLMGCVAET GTVDVGPDSV KSACIEVDIQ QTFFDKTWPR PIDVSKADGI IYPQGRTYSN ITITYQGLF PYQGDHGDMY VYSAGHATGT TPQKLFVANY SQDVKQFANG FVVRIGAAAN STGTVIISPS TSATIRKIYP A FMLGSSVG ...String:
MGILPSPGMP ALLSLVSLLS VLLMGCVAET GTVDVGPDSV KSACIEVDIQ QTFFDKTWPR PIDVSKADGI IYPQGRTYSN ITITYQGLF PYQGDHGDMY VYSAGHATGT TPQKLFVANY SQDVKQFANG FVVRIGAAAN STGTVIISPS TSATIRKIYP A FMLGSSVG NFSDGKMGRF FNHTLVLLPD GCGTLLRAFY CILEPRSGNH CPAGNSYTSF ATYHTPATDC SDGNYNRNAS LN SFKEYFN LRNCTFMYTY NITEDEILEW FGITQTAQGV HLFSSRYVDL YGGNMFQFAT LPVYDTIKYY SIIPHSIRSI QSD RKAWAA FYVYKLQPLT FLLDFSVDGY IRRAIDCGFN DLSQLHCSYE SFDVESGVYS VSSFEAKPSG SVVEQAEGVE CDFS PLLSG TPPQVYNFKR LVFTNCNYNL TKLLSLFSVN DFTCSQISPA AIASNCYSSL ILDYFSYPLS MKSDLSVSSA GPISQ FNYK QSFSNPTCLI LATVPHNLTT ITKPLKYSYI NKCSRLLSDD RTEVPQLVNA NQYSPCVSIV PSTVWEDGDY YRKQLS PLE GGGWLVASGS TVAMTEQLQM GFGITVQYGT DTNSVCPKLE FANDTKIASQ LGNCVEYSLY GVSGRGVFQN CTAVGVR QQ RFVYDAYQNL VGYYSDDGNY YCLRACVSVP VSVIYDKETK THATLFGSVA CEHISSTMSQ YSRSTRSMLK RRDSTYGP L QTPVGCVLGL VNSSLFVEDC KLPLGQSLCA LPDTPSTLTP ASVGSVPGEM RLASIAFNHP IQVDQLNSSY FKLSIPTNF SFGVTQEYIQ TTIQKVTVDC KQYVCNGFQK CEQLLREYGQ FCSKINQALH GANLRQDDSV RNLFASVKSS QSSPIIPGFG GDFNLTLLE PVSISTGSRS ARSAIEDLLF DKVTIADPGY MQGYDDCMQQ GPASARDLIC AQYVAGYKVL PPLMDVNMEA A YTSSLLGS IAGVGWTAGL SSFAAIPFAQ SIFYRLNGVG ITQQVLSENQ KLIANKFNQA LGAMQTGFTT TNEAFQKVQD AV NNNAQAL SKLASELSNT FGAISASIGD IIQRLDPPEQ DAQIDRLING RLTTLNAFVA QQLVRSESAA LSAQLAKDKV NEC VKAQSK RSGFCGQGTH IVSFVVNAPN GLYFMHVGYY PSNHIEVVSA YGLCDAANPT NCIAPVNGYF IKTNNTRIVD EWSY TGSSF YAPEPITSLN TKYVAPQVTY QNISTNLPPP LLGNSTGIDF QDELDEFFKN VSTSIPNFGS LTQINTTLLD LTYEM LSLQ QVVKALNESY IDLKELGNYT YYNKGSGYIP EAPRDGQAYV RKDGEWVLLS TFLGGSGLND IFEAQKIEWH EGGSHH HHH HHH

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Macromolecule #2: Miniprotein cb3_GGGSGGGS_SB175

MacromoleculeName: Miniprotein cb3_GGGSGGGS_SB175 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 16.632369 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MSGSPVKRFV REVLEEAEEA YEKGDRRQFE ELLWLAEWAA RDANDEELEE EIREFEKEVK GGGSGGGSEA LEELEKALRE LKKSTDELE RSTEELEKNP SEDALVENNR LIVENNKIIV EVLRIIAKVL KGSHHWGSTH HHHHH

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 169944
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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