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- EMDB-46922: WEE1 bound to CRBN-DDB1 via compound 10 (CRBN closed conformation) -

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Basic information

Entry
Database: EMDB / ID: EMD-46922
TitleWEE1 bound to CRBN-DDB1 via compound 10 (CRBN closed conformation)
Map dataWEE1-CRBN-DDB1-compound10 closed DeepEMhancer
Sample
  • Complex: Ternary complex of WEE1-compound10-CRBN/DDB1
KeywordsCRBN / molecular glue / WEE1 / E3 ligase / LIGASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.81 Å
AuthorsBaek K / Fischer ES
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA214608 United States
Damon Runyon Cancer Research FoundationDRG-2514-24 United States
CitationJournal: J Am Chem Soc / Year: 2024
Title: Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.
Authors: Hlib Razumkov / Zixuan Jiang / Kheewoong Baek / Inchul You / Qixiang Geng / Katherine A Donovan / Michelle T Tang / Rebecca J Metivier / Nada Mageed / Pooreum Seo / Zhengnian Li / Woong Sub ...Authors: Hlib Razumkov / Zixuan Jiang / Kheewoong Baek / Inchul You / Qixiang Geng / Katherine A Donovan / Michelle T Tang / Rebecca J Metivier / Nada Mageed / Pooreum Seo / Zhengnian Li / Woong Sub Byun / Stephen M Hinshaw / Roman C Sarott / Eric S Fischer / Nathanael S Gray /
Abstract: Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability ...Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 α (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.
History
DepositionSep 6, 2024-
Header (metadata) releaseNov 20, 2024-
Map releaseNov 20, 2024-
UpdateDec 4, 2024-
Current statusDec 4, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46922.png

Downloads & links

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Map

FileDownload / File: emd_46922.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationWEE1-CRBN-DDB1-compound10 closed DeepEMhancer
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 288 pix.
= 316.8 Å		1.1 Å/pix.
x 288 pix.
= 316.8 Å		1.1 Å/pix.
x 288 pix.
= 316.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.0017466787 - 2.0897481
Average (Standard dev.)0.0007698968 (±0.019949744)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 316.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_46922_msk_1.map
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Additional map: 3D Refinement

Fileemd_46922_additional_1.map
Annotation3D Refinement
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Additional map: sharpened map

Fileemd_46922_additional_2.map
Annotationsharpened map
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Half map: halfmap1

Fileemd_46922_half_map_1.map
Annotationhalfmap1
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Half map: halfmap2

Fileemd_46922_half_map_2.map
Annotationhalfmap2
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Sample components

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Entire : Ternary complex of WEE1-compound10-CRBN/DDB1

EntireName: Ternary complex of WEE1-compound10-CRBN/DDB1
Components
  • Complex: Ternary complex of WEE1-compound10-CRBN/DDB1

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Supramolecule #1: Ternary complex of WEE1-compound10-CRBN/DDB1

SupramoleculeName: Ternary complex of WEE1-compound10-CRBN/DDB1 / type: complex / ID: 1 / 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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 53.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.81 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 101857
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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