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- PDB-9w2f: Cryo-EM structure of DDB1-CRBN in complex with dHuR-2 and HuR -

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Basic information

Entry
Database: PDB / ID: 9w2f
TitleCryo-EM structure of DDB1-CRBN in complex with dHuR-2 and HuR
Components
  • DNA damage-binding protein 1
  • ELAV-like protein 1
  • Protein cereblon
KeywordsRNA BINDING PROTEIN / Molecular glue degrader / Complex
Function / homology
Function and homology information


positive regulation of autophagosome size / lncRNA-mediated post-transcriptional gene silencing / negative regulation of miRNA-mediated gene silencing / HuR (ELAVL1) binds and stabilizes mRNA / regulation of stem cell population maintenance / protein-RNA adaptor activity / negative regulation of monoatomic ion transmembrane transport / mRNA 3'-UTR AU-rich region binding / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis ...positive regulation of autophagosome size / lncRNA-mediated post-transcriptional gene silencing / negative regulation of miRNA-mediated gene silencing / HuR (ELAVL1) binds and stabilizes mRNA / regulation of stem cell population maintenance / protein-RNA adaptor activity / negative regulation of monoatomic ion transmembrane transport / mRNA 3'-UTR AU-rich region binding / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / 3'-UTR-mediated mRNA stabilization / mRNA stabilization / miRNA binding / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / mRNA destabilization / WD40-repeat domain binding / lncRNA binding / limb development / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / negative regulation of reproductive process / negative regulation of developmental process / Cul4B-RING E3 ubiquitin ligase complex / ectopic germ cell programmed cell death / ubiquitin ligase complex scaffold activity / locomotory exploration behavior / response to glucose / viral release from host cell / cullin family protein binding / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / positive regulation of viral genome replication / positive regulation of superoxide anion generation / positive regulation of gluconeogenesis / positive regulation of autophagy / positive regulation of translation / sperm principal piece / sperm end piece / mRNA 3'-UTR binding / nucleotide-excision repair / proteasomal protein catabolic process / protein import into nucleus / P-body / positive regulation of protein-containing complex assembly / cell population proliferation / protein homooligomerization / Recognition of DNA damage by PCNA-containing replication complex / regulation of circadian rhythm / Wnt signaling pathway / 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 / Formation of Incision Complex in GG-NER / cytoplasmic stress granule / sperm midpiece / positive regulation of protein catabolic process / cellular response to UV / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / rhythmic process / double-stranded RNA binding / site of double-strand break / Dengue Virus-Host Interactions / Neddylation / cytoplasmic vesicle / Potential therapeutics for SARS / damaged DNA binding / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / chromosome, telomeric region / protein-macromolecule adaptor activity / postsynapse / protein ubiquitination / ribonucleoprotein complex / DNA repair / mRNA binding / apoptotic process / DNA damage response / nucleolus / negative regulation of apoptotic process / protein kinase binding / protein-containing complex binding / perinuclear region of cytoplasm / glutamatergic synapse / endoplasmic reticulum / protein homodimerization activity / protein-containing complex / DNA binding / : / RNA binding / extracellular exosome / nucleoplasm / membrane / metal ion binding / nucleus
Similarity search - Function
HuR, RNA recognition motif 2 / Splicing factor ELAV/Hu / Paraneoplastic encephalomyelitis antigen / 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 ...HuR, RNA recognition motif 2 / Splicing factor ELAV/Hu / Paraneoplastic encephalomyelitis antigen / 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 / 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
: / ELAV-like protein 1 / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsDou, H. / Zhu, Y.
Funding support China, 2items
OrganizationGrant numberCountry
Other private2024 China
Ministry of Education (MoE, China)JYB2025XDXM502 China
CitationJournal: Nature / Year: 2026
Title: Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer.
Authors: Xiaocui Lu / Xiuyun Wang / Zheng Yang / Xusheng Wang / Lin Wang / Chunhui Xu / I-Chung Lo / Chenlu Geng / Lin Wang / Yisheng Pu / Keyu Zhang / Ziqiang Zhu / Lanxin Ye / Jiayuan Huang / ...Authors: Xiaocui Lu / Xiuyun Wang / Zheng Yang / Xusheng Wang / Lin Wang / Chunhui Xu / I-Chung Lo / Chenlu Geng / Lin Wang / Yisheng Pu / Keyu Zhang / Ziqiang Zhu / Lanxin Ye / Jiayuan Huang / Xiaofan Wei / Fang Bai / Yanan Zhu / Xiaobing Qian / Hao Dou / Hexiu Su / Yong Cang /
Abstract: BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF ...BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumour growth, invasion and therapy resistance. dHuR binds to the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its β-hairpin G-loop degron, as revealed by the cryo-electron microscopy structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF-mutant CRC tumours including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat patients with refractory BRAF-mutant CRC.
History
DepositionJul 27, 2025Deposition site: PDBJ / Processing site: PDBC
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: DNA damage-binding protein 1
B: Protein cereblon
C: ELAV-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)180,8445
Polymers180,3643
Non-polymers4812
Water00
1


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

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Components

#1: 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: 127097.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: Q16531
#2: Protein Protein cereblon


Mass: 43882.449 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: Insect cell expression vector pTIE1 (others)
References: UniProt: Q96SW2
#3: Protein ELAV-like protein 1 / Hu-antigen R / HuR


Mass: 9383.622 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELAVL1, HUR
Production host: Cloning vector pET-T7p(-3G)-lacO(SymR+1)-GFP-LVA (others)
References: UniProt: Q15717
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-A1EUN / (3S)-3-[6-[1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]-1-benzofuran-3-yl]piperidine-2,6-dione


Mass: 415.441 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H21N3O4 / 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: Ternary complex of HuR-CRBN/DDB1 with dHuR-2 / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Insect cell expression vector pTIE1 (others)
Buffer solutionpH: 7.4
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: Tecnai F30 / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI F30
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: 4D-STEM / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 484157 / Symmetry type: POINT

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