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- EMDB-27239: Cereblon bound to CC-92480, Focused Refinement -

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Basic information

Entry
Database: EMDB / ID: EMD-27239
TitleCereblon bound to CC-92480, Focused Refinement
Map datafocused refinement of CRBN~DDB1 with Mezigdomide
Sample
  • Complex: Cereblon bound to CC-92480
    • Protein or peptide: Cereblon
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsWatson ER / Lander GC
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
Citation
Journal: Science / Year: 2022
Title: Molecular glue CELMoD compounds are regulators of cereblon conformation.
Authors: Edmond R Watson / Scott Novick / Mary E Matyskiela / Philip P Chamberlain / Andres H de la Peña / Jinyi Zhu / Eileen Tran / Patrick R Griffin / Ingrid E Wertz / Gabriel C Lander /
Abstract: Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior ...Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo-electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)-CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.
#1: Journal: Biorxiv / Year: 2022
Title: Molecular glue CELMoD compounds are allosteric regulators of cereblon conformation
Authors: Watson ER / Novick SJ / Matyskiela ME / Chamberlain PP / de la Pena AH / Zhu JY / Tran E / Griffin PR / Wertz IE / Lander GC
History
DepositionJun 7, 2022-
Header (metadata) releaseJul 20, 2022-
Map releaseJul 20, 2022-
UpdateNov 30, 2022-
Current statusNov 30, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27239.png

Downloads & links

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Map

FileDownload / File: emd_27239.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationfocused refinement of CRBN~DDB1 with Mezigdomide
Voxel sizeX=Y=Z: 1.15 Å
Density
Contour LevelBy AUTHOR: 0.39
Minimum - Maximum-2.615055 - 3.2445776
Average (Standard dev.)-0.0013955495 (±0.04802398)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 257.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27239_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: #1

Fileemd_27239_additional_1.map
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Additional map: Postprocessed with DeepEMhancer

Fileemd_27239_additional_2.map
AnnotationPostprocessed with DeepEMhancer
Projections & Slices
AxesZYX

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Histogram

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Half map: #2

Fileemd_27239_half_map_1.map
Projections & Slices
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Histogram

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Half map: #1

Fileemd_27239_half_map_2.map
Projections & Slices
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Sample components

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Entire : Cereblon bound to CC-92480

EntireName: Cereblon bound to CC-92480
Components
  • Complex: Cereblon bound to CC-92480
    • Protein or peptide: Cereblon

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Supramolecule #1: Cereblon bound to CC-92480

SupramoleculeName: Cereblon bound to CC-92480 / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Cereblon

MacromoleculeName: Cereblon / type: protein_or_peptide / ID: 1 / Details: bound to CC-92480 mezigdomide ligand / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAGEGDQQDA AHNMGNHLPL LPAESEEEDE MEVEDQDSKE AKKPNIINFD TSLPTSHTYL GADMEEFHGR TLHDDDSCQV IPVLPQVMMI LIPGQTLPLQ LFHPQEVSMV RNLIQKDRTF AVLAYSNVQE REAQFGTTAE IYAYREEQDF GIEIVKVKAI GRQRFKVLEL ...String:
MAGEGDQQDA AHNMGNHLPL LPAESEEEDE MEVEDQDSKE AKKPNIINFD TSLPTSHTYL GADMEEFHGR TLHDDDSCQV IPVLPQVMMI LIPGQTLPLQ LFHPQEVSMV RNLIQKDRTF AVLAYSNVQE REAQFGTTAE IYAYREEQDF GIEIVKVKAI GRQRFKVLEL RTQSDGIQQA KVQILPECVL PSTMSAVQLE SLNKCQIFPS KPVSREDQCS YKWWQKYQKR KFHCANLTSW PRWLYSLYDA ETLMDRIKKQ LREWDENLKD DSLPSNPIDF SYRVAACLPI DDVLRIQLLK IGSAIQRLRC ELDIMNKCTS LCCKQCQETE ITTKNEIFSL SLCGPMAAYV NPHGYVHETL TVYKACNLNL IGRPSTEHSW FPGYAWTVAQ CKICASHIGW KFTATKKDMS PQKFWGLTRS ALLPTIPDTE DEISPDKVIL CL

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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

Concentration20 mg/mL
BufferpH: 7
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec. / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 62.5 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 167538
FSC plot (resolution estimation)

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