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- EMDB-22535: SARS-CoV-2 spike in complex with LCB3 (3RBDs open) -

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Basic information

Entry
Database: EMDB / ID: EMD-22535
TitleSARS-CoV-2 spike in complex with LCB3 (3RBDs open)
Map data
SampleDe novo design of picomolar SARS-CoV-2 miniprotein inhibitors:
(SARS-CoV-2 spike) x 2 / (LCB3) x 2
Function / homology
Function and homology information


Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / suppression by virus of host tetherin activity / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / Attachment and Entry / receptor-mediated virion attachment to host cell / endoplasmic reticulum-Golgi intermediate compartment / viral translation / host cell surface receptor binding ...Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / suppression by virus of host tetherin activity / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / Attachment and Entry / receptor-mediated virion attachment to host cell / endoplasmic reticulum-Golgi intermediate compartment / viral translation / host cell surface receptor binding / endocytosis involved in viral entry into host cell / endocytic vesicle membrane / fusion of virus membrane with host plasma membrane / suppression by virus of host type I interferon-mediated signaling pathway / viral protein processing / fusion of virus membrane with host endosome membrane / viral entry into host cell / viral envelope / : / endoplasmic reticulum lumen / host cell plasma membrane / virion membrane / integral component of membrane / identical protein binding
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 / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Spike glycoprotein, betacoronavirus / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Betacoronavirus spike glycoprotein S1, receptor binding / Spike receptor binding domain superfamily, coronavirus / : ...Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Spike glycoprotein, betacoronavirus / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Betacoronavirus spike glycoprotein S1, receptor binding / Spike receptor binding domain superfamily, coronavirus / : / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Spike glycoprotein S2 superfamily, coronavirus / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S2 / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein S2, coronavirus
Similarity search - Domain/homology
Biological speciesSevere acute respiratory syndrome coronavirus 2 / synthetic construct (others) / Severe acute respiratory syndrome-related coronavirus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsPark YJ / Veesler D
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM120553 United States
CitationJournal: Science / Year: 2020
Title: De novo design of picomolar SARS-CoV-2 miniprotein inhibitors.
Authors: Longxing Cao / Inna Goreshnik / Brian Coventry / James Brett Case / Lauren Miller / Lisa Kozodoy / Rita E Chen / Lauren Carter / Alexandra C Walls / Young-Jun Park / Eva-Maria Strauch / ...Authors: Longxing Cao / Inna Goreshnik / Brian Coventry / James Brett Case / Lauren Miller / Lisa Kozodoy / Rita E Chen / Lauren Carter / Alexandra C Walls / Young-Jun Park / Eva-Maria Strauch / Lance Stewart / Michael S Diamond / David Veesler / David Baker /
Abstract: Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising ...Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer-generated scaffolds were either built around an ACE2 helix that interacts with the spike receptor binding domain (RBD) or docked against the RBD to identify new binding modes, and their amino acid sequences were designed to optimize target binding, folding, and stability. Ten designs bound the RBD, with affinities ranging from 100 picomolar to 10 nanomolar, and blocked SARS-CoV-2 infection of Vero E6 cells with median inhibitory concentration (IC) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC ~ 0.16 nanograms per milliliter). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.
History
DepositionSep 2, 2020-
Header (metadata) releaseSep 23, 2020-
Map releaseSep 23, 2020-
UpdateDec 2, 2020-
Current statusDec 2, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_22535.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 400 pix.
= 420. Å
1.05 Å/pix.
x 400 pix.
= 420. Å
1.05 Å/pix.
x 400 pix.
= 420. Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.05 Å
Density
Contour LevelBy AUTHOR: 0.4 / Movie #1: 0.4
Minimum - Maximum-2.025999 - 4.0869455
Average (Standard dev.)0.003564267 (±0.055918016)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 419.99997 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.051.051.05
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z420.000420.000420.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ360360360
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-2.0264.0870.004

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Supplemental data

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Additional map: #1

Fileemd_22535_additional.map
Projections & Slices
AxesZYX

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Density Histograms

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Additional map: #1

Fileemd_22535_additional_1.map
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Half map: #1

Fileemd_22535_half_map_1.map
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Half map: #2

Fileemd_22535_half_map_2.map
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Sample components

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Entire De novo design of picomolar SARS-CoV-2 miniprotein inhibitors

EntireName: De novo design of picomolar SARS-CoV-2 miniprotein inhibitors
Number of Components: 5

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Component #1: protein, De novo design of picomolar SARS-CoV-2 miniprotein inhibitors

ProteinName: De novo design of picomolar SARS-CoV-2 miniprotein inhibitors
Recombinant expression: No

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Component #2: protein, SARS-CoV-2 spike

ProteinName: SARS-CoV-2 spike / Recombinant expression: No
SourceSpecies: Severe acute respiratory syndrome coronavirus 2
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, LCB3

ProteinName: LCB3 / Recombinant expression: No
SourceSpecies: synthetic construct (others)
Source (engineered)Expression System: Escherichia coli K-12 (bacteria)

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Component #4: protein, SARS-CoV-2 spike

ProteinName: SARS-CoV-2 spike / Recombinant expression: No
SourceSpecies: Severe acute respiratory syndrome-related coronavirus
Source (engineered)Expression System: Homo sapiens (human)

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Component #5: protein, LCB3

ProteinName: LCB3 / Recombinant expression: No

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Experimental details

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Sample preparation

SpecimenSpecimen State: Particle / Method: cryo EM
Sample solutionpH: 8
VitrificationCryogen Name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron Source: FIELD EMISSION GUN / Accelerating Voltage: 300 kV / Electron Dose: 70 e/Å2 / Illumination Mode: FLOOD BEAM
LensImaging Mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of Projections: 64285
3D reconstructionSoftware: cryoSPARC / Resolution: 3.2 Å / Resolution Method: FSC 0.143 CUT-OFF

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