[English] 日本語
Yorodumi
- EMDB-29101: EGFR:Degrader:VHL:Elongin-B/C:Cul2 -

+
Open data


ID or keywords:

Loading...

-
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

-
Structure visualization

Supplemental images

emd_29101.png

Downloads & links

-
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 °

-
Supplemental data

-
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)

-
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)

-
Sample components

-
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

-
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)

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
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

-
Electron microscopy

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 0.0015 µm / Nominal defocus min: 0.0005 µm
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

-
Image processing

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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more