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- PDB-12bp: Cryo-EM structure of human DDB1-CRBN-GSPT1 in complex with GT19630 -

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Basic information

Entry
Database: PDB / ID: 12bp
TitleCryo-EM structure of human DDB1-CRBN-GSPT1 in complex with GT19630
Components
  • DNA damage-binding protein 1
  • Eukaryotic peptide chain release factor GTP-binding subunit ERF3A
  • Protein cereblon
KeywordsHYDROLASE / Protein Degrader
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsHuang, J. / Chu, H.F. / Tong, L.
Funding support China, 1items
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, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 26, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
X: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A
Z: Protein cereblon
Y: DNA damage-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)164,8355
Polymers164,1553
Non-polymers6802
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Eukaryotic peptide chain release factor GTP-binding subunit ERF3A / Eukaryotic peptide chain release factor subunit 3a / eRF3a / G1 to S phase transition protein 1 homolog


Mass: 24154.234 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSPT1, ERF3A / Production host: Escherichia coli (E. coli)
References: UniProt: P15170, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#2: Protein Protein cereblon


Mass: 46653.617 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96SW2
#3: Protein DNA damage-binding protein 1 / DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / ...DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / HBV X-associated protein 1 / XAP-1 / UV-damaged DNA-binding factor / UV-damaged DNA-binding protein 1 / UV-DDB 1 / XPE-binding factor / XPE-BF / Xeroderma pigmentosum group E-complementing protein / XPCe


Mass: 93347.078 Da / Num. of mol.: 1
Fragment: UNP residues 1-395,706-1140,UNP residues 1-395,706-1140
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16531
#4: Chemical ChemComp-A1DBR / 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


Mass: 614.650 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H30N6O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Ternary complex of DDB1-CRBN with GSPT1 / Type: COMPLEX / Entity ID: #3, #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
7Cootmodel fitting
12cryoSPARC3D reconstruction
13PHENIX1.20.1_4487model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 291647 / Symmetry type: POINT
RefinementHighest resolution: 2.9 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0043353
ELECTRON MICROSCOPYf_angle_d0.6524543
ELECTRON MICROSCOPYf_dihedral_angle_d5.889493
ELECTRON MICROSCOPYf_chiral_restr0.045519
ELECTRON MICROSCOPYf_plane_restr0.006591

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