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- EMDB-70791: Cryo-EM structure of the DDB1/CRBN-MRT-5702-G3BP2 ternary complex -

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Basic information

Entry
Database: EMDB / ID: EMD-70791
TitleCryo-EM structure of the DDB1/CRBN-MRT-5702-G3BP2 ternary complex
Map data
Sample
  • Complex: DDB1/CRBN-MRT-5702-G3BP2 ternary complex
    • Protein or peptide: Protein cereblon
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Ras GTPase-activating protein-binding protein 2
  • Ligand: ZINC ION
  • Ligand: (1S,3S)-2-[(2-chlorophenyl)methanesulfonyl]-N-{[(4R)-3-(2,4-dioxo-1,3-diazinan-1-yl)imidazo[1,2-a]pyridin-7-yl]methyl}-1-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
Keywordsmolecular glue degrader / neo-substrate / cereblon / E3 ubiquitin ligase / LIGASE
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / UV-damage excision repair / biological process involved in interaction with symbiont / WD40-repeat domain binding / regulation of mitotic cell cycle phase transition / limb development / Cul4A-RING E3 ubiquitin ligase complex ...negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / UV-damage excision repair / biological process involved in interaction with symbiont / WD40-repeat domain binding / regulation of mitotic cell cycle phase transition / limb development / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of reproductive process / negative regulation of developmental process / locomotory exploration behavior / viral release from host cell / cullin family protein binding / mRNA transport / ectopic germ cell programmed cell death / positive regulation of Wnt signaling pathway / positive regulation of viral genome replication / negative regulation of protein-containing complex assembly / proteasomal protein catabolic process / positive regulation of gluconeogenesis / stress granule assembly / sperm end piece / nucleotide-excision repair / molecular condensate scaffold activity / positive regulation of protein-containing complex assembly / Recognition of DNA damage by PCNA-containing replication complex / protein homooligomerization / regulation of circadian rhythm / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Wnt signaling pathway / Formation of Incision Complex in GG-NER / cytoplasmic stress granule / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / positive regulation of protein catabolic process / cellular response to UV / sperm principal piece / rhythmic process / site of double-strand break / sperm midpiece / Neddylation / protein-macromolecule adaptor activity / ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / chromosome, telomeric region / protein ubiquitination / innate immune response / DNA repair / mRNA binding / apoptotic process / DNA damage response / negative regulation of apoptotic process / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / SARS-CoV-2 activates/modulates innate and adaptive immune responses / protein-containing complex / extracellular space / DNA binding / RNA binding / extracellular exosome / nucleoplasm / metal ion binding / membrane / nucleus / cytoplasm / cytosol
Similarity search - Function
G3BP2, RNA recognition motif / Ras GTPase-activating protein-binding protein / Nuclear transport factor 2, eukaryote / Nuclear transport factor 2 domain profile. / Nuclear transport factor 2 (NTF2) domain / Nuclear transport factor 2 domain / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. ...G3BP2, RNA recognition motif / Ras GTPase-activating protein-binding protein / Nuclear transport factor 2, eukaryote / Nuclear transport factor 2 domain profile. / Nuclear transport factor 2 (NTF2) domain / Nuclear transport factor 2 domain / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / : / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / PUA-like superfamily / NTF2-like domain superfamily / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
DNA damage-binding protein 1 / Protein cereblon / Ras GTPase-activating protein-binding protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsQuan C / Petzold G / Gainza P / Tsai J / Bunker RD / Wiedmer L / Donckele EJ
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry.
Authors: Stefano Annunziato / Chao Quan / Etienne J Donckele / Ilaria Lamberto / Richard D Bunker / Mary Zlotosch / Laura Schwander / Anastasia Murthy / Lars Wiedmer / Camille Staehly / Michelle ...Authors: Stefano Annunziato / Chao Quan / Etienne J Donckele / Ilaria Lamberto / Richard D Bunker / Mary Zlotosch / Laura Schwander / Anastasia Murthy / Lars Wiedmer / Camille Staehly / Michelle Matysik / Samuel Gilberto / Despina Kapsitidou / Daric Wible / Gian Marco De Donatis / Peter Trenh / Rohitha SriRamaratnam / Vaik Strande / Raphael Lieberherr / David Lyon / Danielle Steiner / Joao Silva / Reinaldo Almeida / Elena Dolgikh / Bradley DeMarco / Jennifer Tsai / Amine Sadok / Vladislav Zarayskiy / Magnus Walter / Ralph Tiedt / Kevin J Lumb / Debora Bonenfant / Bernhard Fasching / John C Castle / Sharon A Townson / Pablo Gainza / Georg Petzold /
Abstract: Molecular glue degraders (MGDs) are small-molecule compounds that divert E3 ligases to degrade nonnatural substrates called neosubstrates. Clinically effective MGDs bind cereblon (CRBN), a substrate ...Molecular glue degraders (MGDs) are small-molecule compounds that divert E3 ligases to degrade nonnatural substrates called neosubstrates. Clinically effective MGDs bind cereblon (CRBN), a substrate receptor of the Cullin 4-RING E3 ubiquitin ligase (CRL4), and recruit neosubstrates to an MGD-induced neosurface on the CRBN CULT domain through molecular mimicry of a natural CRBN degron. Here, we identify G3BP2 (Ras-GAP SH3 domain-binding protein 2), a neosubstrate that bypasses canonical interactions with CRBN by engaging an unconventional binding site on the CRBN LON domain. The ternary complex interface does not resemble known interactions with CRBN. Instead, CRBN leverages a preexisting protein-protein interaction (PPI) hotspot on the target protein by mimicking an endogenous binding partner of G3BP2. Our findings suggest that composite neosurfaces that mimic and stabilize the footprint of natural PPIs (in short, 'glueprints') could become a viable strategy for the rational expansion of the MGD target repertoire.
History
DepositionMay 23, 2025-
Header (metadata) releaseJan 28, 2026-
Map releaseJan 28, 2026-
UpdateFeb 4, 2026-
Current statusFeb 4, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70791.png

Downloads & links

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Map

FileDownload / File: emd_70791.map.gz / Format: CCP4 / Size: 824 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 600 pix.
= 392.4 Å		0.65 Å/pix.
x 600 pix.
= 392.4 Å		0.65 Å/pix.
x 600 pix.
= 392.4 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.654 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.044
Minimum - Maximum-0.27231437 - 0.4863657
Average (Standard dev.)-0.00018413516 (±0.005867048)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions600600600
Spacing600600600
CellA=B=C: 392.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_70791_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_70791_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : DDB1/CRBN-MRT-5702-G3BP2 ternary complex

EntireName: DDB1/CRBN-MRT-5702-G3BP2 ternary complex
Components
  • Complex: DDB1/CRBN-MRT-5702-G3BP2 ternary complex
    • Protein or peptide: Protein cereblon
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Ras GTPase-activating protein-binding protein 2
  • Ligand: ZINC ION
  • Ligand: (1S,3S)-2-[(2-chlorophenyl)methanesulfonyl]-N-{[(4R)-3-(2,4-dioxo-1,3-diazinan-1-yl)imidazo[1,2-a]pyridin-7-yl]methyl}-1-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

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Supramolecule #1: DDB1/CRBN-MRT-5702-G3BP2 ternary complex

SupramoleculeName: DDB1/CRBN-MRT-5702-G3BP2 ternary complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.55409 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: INFDTSLPTS HTYLGADMEE FHGRTLHDDD SCQVIPVLPQ VMMILIPGQT LPLQLFHPQE VSMVRNLIQK DRTFAVLAYS NVQEREAQF GTTAEIYAYR EEQDFGIEIV KVKAIGRQRF KVLELRTQSD GIQQAKVQIL PECVLPSTMS AVQLESLNKC Q IFPSKPVS ...String:
INFDTSLPTS HTYLGADMEE FHGRTLHDDD SCQVIPVLPQ VMMILIPGQT LPLQLFHPQE VSMVRNLIQK DRTFAVLAYS NVQEREAQF GTTAEIYAYR EEQDFGIEIV KVKAIGRQRF KVLELRTQSD GIQQAKVQIL PECVLPSTMS AVQLESLNKC Q IFPSKPVS REDQCSYKWW QKYQKRKFHC ANLTSWPRWL YSLYDAETLM DRIKKQLREW DENLKDDSLP SNPIDFSYRV AA CLPIDDV LRIQLLKIGS AIQRLRCELD IMNKCTSLCC KQCQETEITT KNEIFSLSLC GPMAAYVNPH GYVHETLTVY KAC NLNLIG RPSTEHSWFP GYAWTVAQCK ICASHIGWKF TATKKDMSPQ KFWGLTRSAL LP

UniProtKB: Protein cereblon

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Macromolecule #2: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.097469 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACIL EYKQSGESID IITRAHGNVQ DRIGRPSETG IIGIIDPECR MIGLRLYDGL FKVIPLDRDN KELKAFNIRL E ELHVIDVK ...String:
MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACIL EYKQSGESID IITRAHGNVQ DRIGRPSETG IIGIIDPECR MIGLRLYDGL FKVIPLDRDN KELKAFNIRL E ELHVIDVK FLYGCQAPTI CFVYQDPQGR HVKTYEVSLR EKEFNKGPWK QENVEAEASM VIAVPEPFGG AIIIGQESIT YH NGDKYLA IAPPIIKQST IVCHNRVDPN GSRYLLGDME GRLFMLLLEK EEQMDGTVTL KDLRVELLGE TSIAECLTYL DNG VVFVGS RLGDSQLVKL NVDSNEQGSY VVAMETFTNL GPIVDMCVVD LERQGQGQLV TCSGAFKEGS LRIIRNGIGI HEHA SIDLP GIKGLWPLRS DPNRETDDTL VLSFVGQTRV LMLNGEEVEE TELMGFVDDQ QTFFCGNVAH QQLIQITSAS VRLVS QEPK ALVSEWKEPQ AKNISVASCN SSQVVVAVGR ALYYLQIHPQ ELRQISHTEM EHEVACLDIT PLGDSNGLSP LCAIGL WTD ISARILKLPS FELLHKEMLG GEIIPRSILM TTFESSHYLL CALGDGALFY FGLNIETGLL SDRKKVTLGT QPTVLRT FR SLSTTNVFAC SDRPTVIYSS NHKLVFSNVN LKEVNYMCPL NSDGYPDSLA LANNSTLTIG TIDEIQKLHI RTVPLYES P RKICYQEVSQ CFGVLSSRIE VQDTSGGTTA LRPSASTQAL SSSVSSSKLF SSSTAPHETS FGEEVEVHNL LIIDQHTFE VLHAHQFLQN EYALSLVSCK LGKDPNTYFI VGTAMVYPEE AEPKQGRIVV FQYSDGKLQT VAEKEVKGAV YSMVEFNGKL LASINSTVR LYEWTTEKEL RTECNHYNNI MALYLKTKGD FILVGDLMRS VLLLAYKPME GNFEEIARDF NPNWMSAVEI L DDDNFLGA ENAFNLFVCQ KDSAATTDEE RQHLQEVGLF HLGEFVNVFC HGSLVMQNLG ETSTPTQGSV LFGTVNGMIG LV TSLSESW YNLLLDMQNR LNKVIKSVGK IEHSFWRSFH TERKTEPATG FIDGDLIESF LDISRPKMQE VVANLQYDDG SGM KREATA DDLIKVVEEL TRIH

UniProtKB: DNA damage-binding protein 1

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Macromolecule #3: Ras GTPase-activating protein-binding protein 2

MacromoleculeName: Ras GTPase-activating protein-binding protein 2 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.19807 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MVMEKPSPLL VGREFVRQYY TLLNKAPEYL HRFYGRNSSY VHGGVDASGK PQEAVYGQND IHHKVLSLNF SECHTKIRHV DAHATLSDG VVVQVMGLLS NSGQPERKFM QTFVLAPEGS VPNKFYVHND MFRYEDEVFG DSEPELDEES EDEVEEEQEE R QPSPEPVQ ...String:
MVMEKPSPLL VGREFVRQYY TLLNKAPEYL HRFYGRNSSY VHGGVDASGK PQEAVYGQND IHHKVLSLNF SECHTKIRHV DAHATLSDG VVVQVMGLLS NSGQPERKFM QTFVLAPEGS VPNKFYVHND MFRYEDEVFG DSEPELDEES EDEVEEEQEE R QPSPEPVQ ENANSGYYEA HPVTNGIEEP LEESSHEPEP EPESETKTEE LKPQVEEKNL EELEEKSTTP PPAEPVSLPQ EP PKAFSWA SVTSKNLPPS GTVSSSGIPP HVKAPVSQPR VEAKPEVQSQ PPRVREQRPR ERPGFPPRGP RPGRGDMEQN DSD NRRIIR YPDSHQLFVG NLPHDIDENE LKEFFMSFGN VVELRINTKG VGGKLPNFGF VVFDDSEPVQ RILIAKPIMF RGEV RLNVE EKKTRAARER ETRGGGDDRR DIRRNDRGPG GPRGIVGGGM MRDRDGRGPP PRGGMAQKLG SGRGTGQMEG RFTGQ RR

UniProtKB: Ras GTPase-activating protein-binding protein 2

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: (1S,3S)-2-[(2-chlorophenyl)methanesulfonyl]-N-{[(4R)-3-(2,4-dioxo...

MacromoleculeName: (1S,3S)-2-[(2-chlorophenyl)methanesulfonyl]-N-{[(4R)-3-(2,4-dioxo-1,3-diazinan-1-yl)imidazo[1,2-a]pyridin-7-yl]methyl}-1-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1CED
Molecular weightTheoretical: 621.106 Da

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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: 7.4
GridModel: C-flat-1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.5056 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.3 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5fqd


Details: PDB ID 5DRV used as startup model for chains C and D
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 565661
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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