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- EMDB-26508: SARS-CoV-2 spike in complex with multivalent miniprotein inhibito... -

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Basic information

Entry
Database: EMDB / ID: EMD-26508
TitleSARS-CoV-2 spike in complex with multivalent miniprotein inhibitor FUS231-P24 (3RBDs open)
Map data
Sample
  • Complex: SARS-CoV-2 spike in complex with multivalent miniprotein inhibitor FUS231-P24 (3RBDs open)
    • Complex: SARS-CoV-2 Hexapro spike protein
      • Protein or peptide: SARS-CoV-2 Hexapro Spike protein
    • Complex: Multivalent miniprotein inhibitor FUS231-P24
      • Protein or peptide: Multivalent miniprotein inhibitor FUS231-P24
Biological speciesSevere acute respiratory syndrome coronavirus 2 / Synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.2 Å
AuthorsPark YJ / Seattle Structural Genomics Center for Infectious Disease (SSGCID) / Veesler D
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)SSGCID United States
CitationJournal: Sci Transl Med / Year: 2022
Title: Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice.
Authors: Andrew C Hunt / James Brett Case / Young-Jun Park / Longxing Cao / Kejia Wu / Alexandra C Walls / Zhuoming Liu / John E Bowen / Hsien-Wei Yeh / Shally Saini / Louisa Helms / Yan Ting Zhao / ...Authors: Andrew C Hunt / James Brett Case / Young-Jun Park / Longxing Cao / Kejia Wu / Alexandra C Walls / Zhuoming Liu / John E Bowen / Hsien-Wei Yeh / Shally Saini / Louisa Helms / Yan Ting Zhao / Tien-Ying Hsiang / Tyler N Starr / Inna Goreshnik / Lisa Kozodoy / Lauren Carter / Rashmi Ravichandran / Lydia B Green / Wadim L Matochko / Christy A Thomson / Bastian Vögeli / Antje Krüger / Laura A VanBlargan / Rita E Chen / Baoling Ying / Adam L Bailey / Natasha M Kafai / Scott E Boyken / Ajasja Ljubetič / Natasha Edman / George Ueda / Cameron M Chow / Max Johnson / Amin Addetia / Mary-Jane Navarro / Nuttada Panpradist / Michael Gale / Benjamin S Freedman / Jesse D Bloom / Hannele Ruohola-Baker / Sean P J Whelan / Lance Stewart / Michael S Diamond / David Veesler / Michael C Jewett / David Baker /
Abstract: New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression ...New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression workflow to rapidly screen and optimize constructs containing multiple computationally designed miniprotein inhibitors of SARS-CoV-2. We found the broadest efficacy was achieved with a homotrimeric version of the 75-residue angiotensin-converting enzyme 2 (ACE2) mimic AHB2 (TRI2-2) designed to geometrically match the trimeric spike architecture. Consistent with the design model, in the cryo-electron microscopy structure TRI2-2 forms a tripod at the apex of the spike protein that engaged all three receptor binding domains simultaneously. TRI2-2 neutralized Omicron (B.1.1.529), Delta (B.1.617.2), and all other variants tested with greater potency than the monoclonal antibodies used clinically for the treatment of COVID-19. TRI2-2 also conferred prophylactic and therapeutic protection against SARS-CoV-2 challenge when administered intranasally in mice. Designed miniprotein receptor mimics geometrically arrayed to match pathogen receptor binding sites could be a widely applicable antiviral therapeutic strategy with advantages over antibodies in greater resistance to viral escape and antigenic drift, and advantages over native receptor traps in lower chances of autoimmune responses.
History
DepositionMar 26, 2022-
Header (metadata) releaseJun 8, 2022-
Map releaseJun 8, 2022-
UpdateJun 8, 2022-
Current statusJun 8, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26508.png

Downloads & links

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Map

FileDownload / File: emd_26508.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.16 Å
Density
Contour LevelBy AUTHOR: 0.34
Minimum - Maximum-0.5443014 - 1.5458364
Average (Standard dev.)-0.00020902518 (±0.03983033)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 464.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_26508_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_26508_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_26508_half_map_2.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Sample components

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Entire : SARS-CoV-2 spike in complex with multivalent miniprotein inhibito...

EntireName: SARS-CoV-2 spike in complex with multivalent miniprotein inhibitor FUS231-P24 (3RBDs open)
Components
  • Complex: SARS-CoV-2 spike in complex with multivalent miniprotein inhibitor FUS231-P24 (3RBDs open)
    • Complex: SARS-CoV-2 Hexapro spike protein
      • Protein or peptide: SARS-CoV-2 Hexapro Spike protein
    • Complex: Multivalent miniprotein inhibitor FUS231-P24
      • Protein or peptide: Multivalent miniprotein inhibitor FUS231-P24

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Supramolecule #1: SARS-CoV-2 spike in complex with multivalent miniprotein inhibito...

SupramoleculeName: SARS-CoV-2 spike in complex with multivalent miniprotein inhibitor FUS231-P24 (3RBDs open)
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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Supramolecule #2: SARS-CoV-2 Hexapro spike protein

SupramoleculeName: SARS-CoV-2 Hexapro spike protein / type: complex / Chimera: Yes / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: Multivalent miniprotein inhibitor FUS231-P24

SupramoleculeName: Multivalent miniprotein inhibitor FUS231-P24 / type: complex / Chimera: Yes / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Synthetic construct (others)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Macromolecule #1: SARS-CoV-2 Hexapro Spike protein

MacromoleculeName: SARS-CoV-2 Hexapro Spike protein / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS NVTWFHAIHV SGTNGTKRFD NPVLPFNDG VYFASTEKSN IIRGWIFGTT LDSKTQSLLI VNNATNVVIK VCEFQFCNDP FLGVYYHKNN KSWMESEFRV Y SSANNCTF ...String:
MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS NVTWFHAIHV SGTNGTKRFD NPVLPFNDG VYFASTEKSN IIRGWIFGTT LDSKTQSLLI VNNATNVVIK VCEFQFCNDP FLGVYYHKNN KSWMESEFRV Y SSANNCTF EYVSQPFLMD LEGKQGNFKN LREFVFKNID GYFKIYSKHT PINLVRDLPQ GFSALEPLVD LPIGINITRF QT LLALHRS YLTPGDSSSG WTAGAAAYYV GYLQPRTFLL KYNENGTITD AVDCALDPLS ETKCTLKSFT VEKGIYQTSN FRV QPTESI VRFPNITNLC PFGEVFNATR FASVYAWNRK RISNCVADYS VLYNSASFST FKCYGVSPTK LNDLCFTNVY ADSF VIRGD EVRQIAPGQT GKIADYNYKL PDDFTGCVIA WNSNNLDSKV GGNYNYLYRL FRKSNLKPFE RDISTEIYQA GSTPC NGVE GFNCYFPLQS YGFQPTNGVG YQPYRVVVLS FELLHAPATV CGPKKSTNLV KNKCVNFNFN GLTGTGVLTE SNKKFL PFQ QFGRDIADTT DAVRDPQTLE ILDITPCSFG GVSVITPGTN TSNQVAVLYQ DVNCTEVPVA IHADQLTPTW RVYSTGS NV FQTRAGCLIG AEHVNNSYEC DIPIGAGICA SYQTQTNSPG SASSVASQSI IAYTMSLGAE NSVAYSNNSI AIPTNFTI S VTTEILPVSM TKTSVDCTMY ICGDSTECSN LLLQYGSFCT QLNRALTGIA VEQDKNTQEV FAQVKQIYKT PPIKDFGGF NFSQILPDPS KPSKRSPIED LLFNKVTLAD AGFIKQYGDC LGDIAARDLI CAQKFNGLTV LPPLLTDEMI AQYTSALLAG TITSGWTFG AGPALQIPFP MQMAYRFNGI GVTQNVLYEN QKLIANQFNS AIGKIQDSLS STPSALGKLQ DVVNQNAQAL N TLVKQLSS NFGAISSVLN DILSRLDPPE AEVQIDRLIT GRLQSLQTYV TQQLIRAAEI RASANLAATK MSECVLGQSK RV DFCGKGY HLMSFPQSAP HGVVFLHVTY VPAQEKNFTT APAICHDGKA HFPREGVFVS NGTHWFVTQR NFYEPQIITT DNT FVSGNC DVVIGIVNNT VYDPLQPELD SFKEELDKYF KNHTSPDVDL GDISGINASV VNIQKEIDRL NEVAKNLNES LIDL QELGK YEQGSGYIPE APRDGQAYVR KDGEWVLLST FLGRSLEVLF QGPGHHHHHH HHSAWSHPQF EKGGGSGGGG SGGSA WSHP QFEK

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Macromolecule #2: Multivalent miniprotein inhibitor FUS231-P24

MacromoleculeName: Multivalent miniprotein inhibitor FUS231-P24 / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Synthetic construct (others)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEKKI NLDE LHMQMTDLVY EALHFAKDEE FQKHVFQLFE KATKAYKNKD RQKLEKVVEE LKELLERLLS GGASPAAPA PASPAAPAPS APAGG ELEE QVMHVLDQVS ELAHELLHKL TGEELERAAY FNWWATEMML ELIKSDDERE IREIEEEAAR ILEHLEELAR T ...String:
MEKKI NLDE LHMQMTDLVY EALHFAKDEE FQKHVFQLFE KATKAYKNKD RQKLEKVVEE LKELLERLLS GGASPAAPA PASPAAPAPS APAGG ELEE QVMHVLDQVS ELAHELLHKL TGEELERAAY FNWWATEMML ELIKSDDERE IREIEEEAAR ILEHLEELAR T GGASPAAP APASPAAPAP SAPAGG DKE NVLQKIYEIM KELERLGHAE ASMQVSDLIY EFMKTKDENL LEEAERLLEE VKR GGSGSS GSAWSHPQFE KGGGSGGGSG GSAWSHPQFE K

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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 GLACIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm

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Image processing

Startup modelType of model: OTHER / Details: cryoSPARC ab initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 18084
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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