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- EMDB-76291: Cryo-EM structure of human DDB1-CRBN-GSPT1 in complex with GT19630 -

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Entry
Database: EMDB / ID: EMD-76291
TitleCryo-EM structure of human DDB1-CRBN-GSPT1 in complex with GT19630
Map datastructure of human DDB1-CRBN-GSPT1 in complex with GT19630
Sample
  • Complex: Ternary complex of DDB1-CRBN with GSPT1
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A
    • Protein or peptide: Protein cereblon
  • Ligand: 2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-N-[(4-{[2-(9H-pyrido[2,3-b]indol-9-yl)acetamido]methyl}phenyl)methyl]-2,3-dihydro-1H-isoindole-5-carboxamide
  • Ligand: ZINC ION
KeywordsProtein Degrader / HYDROLASE
Function / homology
Function and homology information


translation release factor complex / regulation of translational termination / translation release factor activity / negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / epigenetic programming in the zygotic pronuclei / protein methylation / UV-damage excision repair ...translation release factor complex / regulation of translational termination / translation release factor activity / negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / epigenetic programming in the zygotic pronuclei / protein methylation / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cytokinesis / regulation of mitotic cell cycle phase transition / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / WD40-repeat domain binding / regulation of cell cycle phase transition / locomotory exploration behavior / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / regulation of cellular response to stress / limb development / viral release from host cell / cullin family protein binding / Eukaryotic Translation Termination / positive regulation of Wnt signaling pathway / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / negative regulation of protein-containing complex assembly / regulation of DNA-templated DNA replication initiation / positive regulation of viral genome replication / positive regulation of gluconeogenesis / translational termination / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / regulation of embryonic development / replication fork processing / G1/S transition of mitotic cell cycle / proteasomal protein catabolic process / epigenetic regulation of gene expression / positive regulation of protein-containing complex assembly / nucleotide-excision repair / regulation of autophagy / Recognition of DNA damage by PCNA-containing replication complex / regulation of circadian rhythm / cell population proliferation / 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 / Regulation of expression of SLITs and ROBOs / Formation of Incision Complex in GG-NER / positive regulation of protein catabolic process / cellular response to UV / cytosolic ribosome / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / regulation of cell population proliferation / rhythmic process / site of double-strand break / Neddylation / spermatogenesis / ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of apoptotic process / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / transmembrane transporter binding / protein-macromolecule adaptor activity / chromosome, telomeric region / protein ubiquitination / translation / DNA repair / GTPase activity / DNA damage response / nucleolus / GTP binding / protein-containing complex binding / perinuclear region of cytoplasm / protein-containing complex / DNA binding / : / RNA binding / extracellular exosome / nucleoplasm / membrane / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / GTP-eEF1A C-terminal domain-like / : / 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 ...: / GTP-eEF1A C-terminal domain-like / : / 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) / Translation elongation factor EF1A/initiation factor IF2gamma, C-terminal / : / 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 / Tr-type G domain, conserved site / Translational (tr)-type guanine nucleotide-binding (G) domain signature. / Translation elongation factor EFTu-like, domain 2 / Elongation factor Tu domain 2 / Translational (tr)-type GTP-binding domain / Elongation factor Tu GTP binding domain / Translational (tr)-type guanine nucleotide-binding (G) domain profile. / Translation protein, beta-barrel domain superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Eukaryotic peptide chain release factor GTP-binding subunit ERF3A / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsHuang J / Chu HF / Tong L
Funding support China, 1 items
OrganizationGrant numberCountry
Other private China
CitationJournal: Blood / Year: 2026
Title: Dual MYC and GSPT1 Protein Degrader for MYC-Driven Hematologic Malignancies.
Authors: Yuki Nishida / Valeria Impedovo / Edward Ayoub / Natalia Baran / Darah A Scruggs / Hideaki Mizuno / Shayaun Khazaei / Lauren B Ostermann / Kazuharu Kamachi / Liang Zhang / Jo Ishizawa / ...Authors: Yuki Nishida / Valeria Impedovo / Edward Ayoub / Natalia Baran / Darah A Scruggs / Hideaki Mizuno / Shayaun Khazaei / Lauren B Ostermann / Kazuharu Kamachi / Liang Zhang / Jo Ishizawa / Sandeep Singh / Andrea D Bedoy / Po Yee Mak / Bing Z Carter / Eiji Sugihara / Tetsuya Takimoto / Youzhi Tong / Honghua Yan / Dong Chen / Ji Huang / Hsu-Feng Chu / Liang Tong / Zamal Ahmed / Sarita Namjoshi / John Tainer / Mihai Gagea / Thomas Huynh / Abhishek Maiti / Koji Sasaki / Branko Cuglievan / Steffen Boettcher / Torsten Haferlach / Stefano Tiziani / Liandong Ma / Michael Andreeff /
Abstract: Direct targeting of the oncoprotein MYC has not yet been successful. We here report a novel dual protein degrader, GT19630, which binds directly to MYC and G1 to S phase transition protein 1 (GSPT1). ...Direct targeting of the oncoprotein MYC has not yet been successful. We here report a novel dual protein degrader, GT19630, which binds directly to MYC and G1 to S phase transition protein 1 (GSPT1). GT19630 disrupts a novel feedforward loop of MYC and GSPT1, where MYC promotes transcription of GSPT1, and GSPT1 senses the stop codon of MYC to properly terminate its translation. The agent induces integrated stress response and abrogates oxidative phosphorylation through inhibition of the TCA cycle, resulting in apoptosis. GT19630 has superior activity compared to GSPT1- targeting molecular glues. GT19630 induces profound anti-proliferative effects and apoptosis at low nanomolar concentrations in a multitude of leukemia and lymphoma cell lines and primary samples, including those with TP53 mutations. GT19630 is highly active in vivo in models of therapy-resistant hematologic malignancies, including Burkitt's lymphoma, acute myeloid leukemia (AML) and multiple myeloma. CD34+ AML blasts overexpress MYC protein compared to normal hematopoietic stem/progenitor cells (HSPCs) and GT19630 induces greater cytotoxicity in AML cells compared to normal HSPCs. Further, GT19630 restores sensitivity to venetoclax and profoundly prolongs survival in vivo in venetoclax-resistant AML. GT19630 was well tolerated in humanized Crbn mice. In conclusion, our data support the development of the MYC/GSPT1 degrader GT19630 as a therapeutic strategy of MYC-driven hematologic malignancies.
History
DepositionMar 25, 2026-
Header (metadata) releaseAug 26, 2026-
Map releaseAug 26, 2026-
UpdateAug 26, 2026-
Current statusAug 26, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76291.png

Downloads & links

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Map

FileDownload / File: emd_76291.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationstructure of human DDB1-CRBN-GSPT1 in complex with GT19630
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 320 pix.
= 265.6 Å		0.83 Å/pix.
x 320 pix.
= 265.6 Å		0.83 Å/pix.
x 320 pix.
= 265.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.16
Minimum - Maximum-1.681528 - 1.9020134
Average (Standard dev.)0.00006266548 (±0.037829924)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 265.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Additional Map

Fileemd_76291_additional_1.map
AnnotationAdditional Map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map A

Fileemd_76291_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_76291_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Ternary complex of DDB1-CRBN with GSPT1

EntireName: Ternary complex of DDB1-CRBN with GSPT1
Components
  • Complex: Ternary complex of DDB1-CRBN with GSPT1
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A
    • Protein or peptide: Protein cereblon
  • Ligand: 2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-N-[(4-{[2-(9H-pyrido[2,3-b]indol-9-yl)acetamido]methyl}phenyl)methyl]-2,3-dihydro-1H-isoindole-5-carboxamide
  • Ligand: ZINC ION

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Supramolecule #1: Ternary complex of DDB1-CRBN with GSPT1

SupramoleculeName: Ternary complex of DDB1-CRBN with GSPT1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #3, #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A

MacromoleculeName: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.154234 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSSHHHHHH SSGLVPRGSH MGPIRLPIVD KYKDMGTVVL GKLESGSICK GQQLVMMPNK HNVEVLGILS DDVETDTVAP GENLKIRLK GIEEEEILPG FILCDPNNLC HSGRTFDAQI VIIEHKSIIC PGYNAVLHIH TCIEEVEITA LICLVDKKSG E KSKTRPRF ...String:
MGSSHHHHHH SSGLVPRGSH MGPIRLPIVD KYKDMGTVVL GKLESGSICK GQQLVMMPNK HNVEVLGILS DDVETDTVAP GENLKIRLK GIEEEEILPG FILCDPNNLC HSGRTFDAQI VIIEHKSIIC PGYNAVLHIH TCIEEVEITA LICLVDKKSG E KSKTRPRF VKQDQVCIAR LRTAGTICLE TFKDFPQMGR FTLRDEGKTI AIGKVLKLVP

UniProtKB: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A

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Macromolecule #2: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.653617 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: SNMEAKKPNI INFDTSLPTS HTYLGADMEE FHGRTLHDDD SCQVIPVLPQ VMMILIPGQT LPLQLFHPQE VSMVRNLIQK DRTFAVLAY SNVQEREAQF GTTAEIYAYR EEQDFGIEIV KVKAIGRQRF KVLELRTQSD GIQQAKVQIL PECVLPSTMS A VQLESLNK ...String:
SNMEAKKPNI INFDTSLPTS HTYLGADMEE FHGRTLHDDD SCQVIPVLPQ VMMILIPGQT LPLQLFHPQE VSMVRNLIQK DRTFAVLAY SNVQEREAQF GTTAEIYAYR EEQDFGIEIV KVKAIGRQRF KVLELRTQSD GIQQAKVQIL PECVLPSTMS A VQLESLNK CQIFPSKPVS REDQCSYKWW QKYQKRKFHC ANLTSWPRWL YSLYDAETLM DRIKKQLREW DENLKDDSLP SN PIDFSYR VAACLPIDDV LRIQLLKIGS AIQRLRCELD IMNKCTSLCC KQCQETEITT KNEIFSLSLC GPMAAYVNPH GYV HETLTV YKACNLNLIG RPSTEHSWFP GYAWTVAQCK ICASHIGWKF TATKKDMSPQ KFWGLTRSAL LPTIPDTEDE ISPD KVILC L

UniProtKB: Protein cereblon

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Macromolecule #3: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.347078 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
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 LRIIRNGIGG NGNS GEIQK LHIRTVPLYE SPRKICYQEV SQCFGVLSSR IEVQDTSGGT TALRPSASTQ ALSSSVSSSK LFSSSTAPHE TSFGE EVEV HNLLIIDQHT FEVLHAHQFL QNEYALSLVS CKLGKDPNTY FIVGTAMVYP EEAEPKQGRI VVFQYSDGKL QTVAEK EVK GAVYSMVEFN GKLLASINST VRLYEWTTEK ELRTECNHYN NIMALYLKTK GDFILVGDLM RSVLLLAYKP MEGNFEE IA RDFNPNWMSA VEILDDDNFL GAENAFNLFV CQKDSAATTD EERQHLQEVG LFHLGEFVNV FCHGSLVMQN LGETSTPT Q GSVLFGTVNG MIGLVTSLSE SWYNLLLDMQ NRLNKVIKSV GKIEHSFWRS FHTERKTEPA TGFIDGDLIE SFLDISRPK MQEVVANLQY DDGSGMKREA TADDLIKVVE ELTRIH

UniProtKB: DNA damage-binding protein 1, DNA damage-binding protein 1

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Macromolecule #4: 2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-N-[(4-{[2-(9H-pyrido[2,3-b...

MacromoleculeName: 2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-N-[(4-{[2-(9H-pyrido[2,3-b]indol-9-yl)acetamido]methyl}phenyl)methyl]-2,3-dihydro-1H-isoindole-5-carboxamide
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1DBR
Molecular weightTheoretical: 614.65 Da

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6xk9

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 291647
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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