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- PDB-9y7d: Cereblon with Golcadomide and Ikaros ZF1-2-3 -

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Basic information

Entry
Database: PDB / ID: 9y7d
TitleCereblon with Golcadomide and Ikaros ZF1-2-3
Components
  • DNA-binding protein Ikaros
  • Protein cereblon
KeywordsLIGASE / Liganded Cereblon Ligase Substrate
Function / homology
Function and homology information


lymphocyte differentiation / negative regulation of monoatomic ion transmembrane transport / NOTCH3 Intracellular Domain Regulates Transcription / limb development / Cul4A-RING E3 ubiquitin ligase complex / mesoderm development / locomotory exploration behavior / positive regulation of Wnt signaling pathway / pericentric heterochromatin / negative regulation of protein-containing complex assembly ...lymphocyte differentiation / negative regulation of monoatomic ion transmembrane transport / NOTCH3 Intracellular Domain Regulates Transcription / limb development / Cul4A-RING E3 ubiquitin ligase complex / mesoderm development / locomotory exploration behavior / positive regulation of Wnt signaling pathway / pericentric heterochromatin / negative regulation of protein-containing complex assembly / erythrocyte differentiation / positive regulation of protein-containing complex assembly / chromatin organization / Potential therapeutics for SARS / transmembrane transporter binding / proteasome-mediated ubiquitin-dependent protein catabolic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein ubiquitination / DNA-binding transcription factor activity / protein domain specific binding / negative regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / perinuclear region of cytoplasm / protein-containing complex / DNA binding / zinc ion binding / nucleoplasm / membrane / metal ion binding / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
: / 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) ...: / 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) / PUA-like superfamily / Zinc finger, C2H2 type / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type
Similarity search - Domain/homology
: / DNA-binding protein Ikaros / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsWatson, E.R. / Lander, G.C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Blood Cancer Discov / Year: 2026
Title: Golcadomide: An Oral CELMoD Agent Targeting IKZF1/3 for Diffuse Large B-cell Lymphoma.
Authors: Zhongying Mo / Lynda Groocock / Scott Wood / Diana Jankeel / Derek Mendy / Edmond R Watson / Yan Kai / Gauri Deb / Marjorie Cote / Preethi Janardhanan / Álvaro Fernández-Deudero / Leo ...Authors: Zhongying Mo / Lynda Groocock / Scott Wood / Diana Jankeel / Derek Mendy / Edmond R Watson / Yan Kai / Gauri Deb / Marjorie Cote / Preethi Janardhanan / Álvaro Fernández-Deudero / Leo Barnes / Sophie Peng / Matthew Groza / Evgenia Kalashnikova / Michael Angelo / Jinyi Zhu / Ryan Galasso / In Sock Jang / Manuel Sanchez Castillo / Celia Fontanillo / Geraldine Polido / Andy Christoforou / Timothy Kercher / Gabriel C Lander / Kai Wang / Rama Krishna Narla / Soraya Carrancio / Daniel W Pierce / Mark Rolfe / Neil Bence / Antonia Lopez-Girona /
Abstract: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease with limited treatment options and a poor prognosis, especially for patients refractory to standard therapies. We ...Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease with limited treatment options and a poor prognosis, especially for patients refractory to standard therapies. We report the discovery of golcadomide (CC-99282), an oral cereblon-modulating CELMoD agent designed using target-specific knowledge and optimized pharmacologic properties for the treatment of DLBCL. Golcadomide exhibited rapid, deep, and sustained degradation of transcription factors IKZF1 and IKZF3, surpassing the antitumor activity of the IMiD agent lenalidomide in preclinical models. In human lymphoma cell lines, golcadomide downregulated MYC, activated IFN-stimulated genes, and promoted antiproliferation, apoptosis, and immunogenic cell death. In mouse xenografts, golcadomide preferentially distributed to tissues known to be affected by lymphoma, resulting in enhanced tumor regression and tumor-free outcomes. Pharmacologic and CRISPR screening further revealed genes and pathways underlying golcadomide's antitumor efficacy. These findings supported golcadomide as a promising drug candidate for DLBCL, providing a strong rationale for future golcadomide-based regimens.
SIGNIFICANCE: Golcadomide is an oral cereblon-modulating agent for the treatment of DLBCL. It exhibited rapid, deep, and sustained degradation of IKZF1 and IKZF3, preferentially accumulated in ...SIGNIFICANCE: Golcadomide is an oral cereblon-modulating agent for the treatment of DLBCL. It exhibited rapid, deep, and sustained degradation of IKZF1 and IKZF3, preferentially accumulated in lymphoma residence tissues, and delivered robust antitumor activity. These results provide a strong rationale for continued clinical investigation of golcadomide for patients with DLBCL.
History
DepositionSep 9, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 15, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.1Apr 29, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Protein cereblon
C: DNA-binding protein Ikaros
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,8695
Polymers59,2022
Non-polymers6663
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Protein cereblon


Mass: 46596.566 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2
#2: Protein DNA-binding protein Ikaros / Ikaros family zinc finger protein 1 / Lymphoid transcription factor LyF-1


Mass: 12605.633 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IKZF1, IK1, IKAROS, LYF1, ZNFN1A1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q13422
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-A1AF4 / Golcadomide


Mass: 535.567 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H30FN5O5 / Feature type: SUBJECT OF INVESTIGATION
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: Cereblon with Golcadomide with Ikaros ZF1-2-3 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: NITROGEN

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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: 0 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 170954 / Symmetry type: POINT

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