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- EMDB-29101: EGFR:Degrader:VHL:Elongin-B/C:Cul2 -

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Basic information

Entry
Database: EMDB / ID: EMD-29101
TitleEGFR:Degrader:VHL:Elongin-B/C:Cul2
Map dataEGFR:Degrader:VHL:Elongin-B/C:Cul2
Sample
  • Complex: Degrader induced complex between EGFR and Cul2:Rbx1:VHL:Elongin-B/C
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.2 Å
AuthorsRosenberg SC
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Cell Chem Biol / Year: 2023
Title: Ternary complex dissociation kinetics contribute to mutant-selective EGFR degradation.
Authors: Scott C Rosenberg / Frances Shanahan / Sayumi Yamazoe / Marc Kschonsak / Yi J Zeng / James Lee / Emile Plise / Ivana Yen / Christopher M Rose / John G Quinn / Lewis J Gazzard / Benjamin T ...Authors: Scott C Rosenberg / Frances Shanahan / Sayumi Yamazoe / Marc Kschonsak / Yi J Zeng / James Lee / Emile Plise / Ivana Yen / Christopher M Rose / John G Quinn / Lewis J Gazzard / Benjamin T Walters / Donald S Kirkpatrick / Steven T Staben / Scott A Foster / Shiva Malek /
Abstract: Targeted degradation of proteins by chimeric heterobifunctional degraders has emerged as a major drug discovery paradigm. Despite the increased interest in this approach, the criteria dictating ...Targeted degradation of proteins by chimeric heterobifunctional degraders has emerged as a major drug discovery paradigm. Despite the increased interest in this approach, the criteria dictating target protein degradation by a degrader remain poorly understood, and potent target engagement by a degrader does not strongly correlate with target degradation. In this study, we present the biochemical characterization of an epidermal growth factor receptor (EGFR) degrader that potently binds both wild-type and mutant EGFR, but only degrades EGFR mutant variants. Mechanistic studies reveal that ternary complex half-life strongly correlates with processive ubiquitination with purified components and mutant-selective degradation in cells. We present cryoelectron microscopy and hydrogen-deuterium exchange mass spectroscopy data on wild-type and mutant EGFR ternary complexes, which demonstrate that potent target degradation can be achieved in the absence of stable compound-induced protein-protein interactions. These results highlight the importance of considering target conformation during degrader development as well as leveraging heterobifunctional ligand binding kinetics to achieve robust target degradation.
History
DepositionDec 14, 2022-
Header (metadata) releaseMar 8, 2023-
Map releaseMar 8, 2023-
UpdateMar 8, 2023-
Current statusMar 8, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29101.png

Downloads & links

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Map

FileDownload / File: emd_29101.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationEGFR:Degrader:VHL:Elongin-B/C:Cul2
Voxel sizeX=Y=Z: 1.5 Å
Density
Contour LevelBy AUTHOR: 0.174
Minimum - Maximum-0.61092263 - 1.1402276
Average (Standard dev.)0.009351742 (±0.03507309)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 300.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_29101_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_29101_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Degrader induced complex between EGFR and Cul2:Rbx1:VHL:Elongin-B/C

EntireName: Degrader induced complex between EGFR and Cul2:Rbx1:VHL:Elongin-B/C
Components
  • Complex: Degrader induced complex between EGFR and Cul2:Rbx1:VHL:Elongin-B/C

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Supramolecule #1: Degrader induced complex between EGFR and Cul2:Rbx1:VHL:Elongin-B/C

SupramoleculeName: Degrader induced complex between EGFR and Cul2:Rbx1:VHL:Elongin-B/C
type: complex / ID: 1 / Chimera: Yes / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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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

Concentration0.5 mg/mL
BufferpH: 7.5 / Details: 200 mM NaCl, 20 mM Tris7.5, 1 mM TCEP
GridModel: C-flat-1.2/1.3
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Number real images: 1848 / Average exposure time: 20.0 sec. / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 0.0015 µm / Nominal defocus min: 0.0005 µm

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 55053
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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