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- PDB-10ay: Cryo-EM structure of CRBN-DDB1 in complex with HBS1L and TNG961 -

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Basic information

Entry
Database: PDB / ID: 10ay
TitleCryo-EM structure of CRBN-DDB1 in complex with HBS1L and TNG961
Components
  • DNA damage-binding protein 1
  • HBS1-like protein
  • Protein cereblon
KeywordsCYTOSOLIC PROTEIN / FOCAD / ribosome / PELO / ubiquitin
Function / homology
Function and homology information


Dom34-Hbs1 complex / nuclear-transcribed mRNA catabolic process, no-go decay / mRNA decay by 3' to 5' exoribonuclease / negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / ribosome disassembly / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / UV-damage excision repair / biological process involved in interaction with symbiont ...Dom34-Hbs1 complex / nuclear-transcribed mRNA catabolic process, no-go decay / mRNA decay by 3' to 5' exoribonuclease / negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / ribosome disassembly / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / UV-damage excision repair / biological process involved in interaction with symbiont / limb development / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / 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 / ectopic germ cell programmed cell death / translation elongation factor activity / positive regulation of Wnt signaling pathway / positive regulation of viral genome replication / negative regulation of protein-containing complex assembly / proteasomal protein catabolic process / rescue of stalled cytosolic ribosome / positive regulation of gluconeogenesis / cytosolic ribosome / nucleotide-excision repair / sperm end piece / positive regulation of protein-containing complex assembly / regulation of circadian rhythm / Recognition of DNA damage by PCNA-containing replication complex / 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 / 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 / rhythmic process / regulation of translation / site of double-strand break / sperm principal piece / Neddylation / sperm midpiece / Potential therapeutics for SARS / ubiquitin-dependent protein catabolic process / damaged DNA binding / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / transmembrane transporter binding / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / chromosome, telomeric region / protein ubiquitination / translation / DNA repair / GTPase activity / apoptotic process / DNA damage response / negative regulation of apoptotic process / GTP binding / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / signal transduction / protein-containing complex / : / DNA binding / extracellular exosome / nucleoplasm / membrane / metal ion binding / nucleus / cytoplasm / cytosol
Similarity search - Function
HBS1-like protein, N-terminal domain superfamily / HBS1-like protein, N-terminal / HBS1 N-terminus / : / GTP-eEF1A C-terminal domain-like / : / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. ...HBS1-like protein, N-terminal domain superfamily / HBS1-like protein, N-terminal / HBS1 N-terminus / : / 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) / : / 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 / Translation elongation factor EF1A/initiation factor IF2gamma, C-terminal / PUA-like superfamily / 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
: / DNA damage-binding protein 1 / Protein cereblon / HBS1-like protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsWhittington, D.A.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Cancer Discov / Year: 2026
Title: TNG961 is a selective oral HBS1L molecular glue degrader for the treatment of FOCAD-deleted cancers.
Authors: Hilary E Nicholson / Douglas A Whittington / Frank J Bruzzese / Katherine Lazarides / Lauren Catherine M Martires / Matthew R Tonini / Helena N Jenkins / Minjie Zhang / Preksha Shahagadkar / ...Authors: Hilary E Nicholson / Douglas A Whittington / Frank J Bruzzese / Katherine Lazarides / Lauren Catherine M Martires / Matthew R Tonini / Helena N Jenkins / Minjie Zhang / Preksha Shahagadkar / Charlotte B Pratt / Kimberly J Briggs / Patrick McCarren / Alice Tsai / Madhavi Bandi / Chengyin Min / Alan Huang / Hongxiang Zhang / Samuel R Meier / Binzhang Shen / Yi Yu / Colin Liang / Yong Liu / Teng Teng / John Zhang / Adam Crystal / William D Mallender / Xinyuan Edward Wu / John P Maxwell / Jannik N Andersen /
Abstract: When tumor suppressor genes are lost through chromosomal deletion, deletion of adjacent genes can generate therapeutic vulnerabilities. MTAP is frequently co-deleted with the Chr9p21 tumor suppressor ...When tumor suppressor genes are lost through chromosomal deletion, deletion of adjacent genes can generate therapeutic vulnerabilities. MTAP is frequently co-deleted with the Chr9p21 tumor suppressor gene CDKN2A, creating synthetic lethal dependency on PRMT5. Telomeric to MTAP lies FOCAD, whose loss induces dependency on the HBS1L/PELO ribosome-rescue complex for translational maintenance. FOCAD is deleted in ~1/3 of MTAP-deleted cancers. We screened an IMiD-focused diversity library and identified a weak hit that bound cereblon, promoted HBS1L-CRBN-compound complex formation, and induced E3-ligase-dependent HBS1L ubiquitination and degradation. Guided by cryo-EM structures and proteome selectivity we developed TNG961, a potent, selective HBS1L degrader that disrupts the HBS1L/PELO complex, inducing translational arrest, unfolded protein response activation, and growth inhibition in FOCAD-negative models. Oral administration of TNG961 regresses FOCAD-negative xenografts, including PRMT5 inhibitor-refractory models, establishing HBS1L degradation as a strategy to exploit FOCAD loss and supporting clinical evaluation of TNG961 as a first-in-class precision oncology therapeutic.
History
DepositionJan 9, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: HBS1-like protein
B: Protein cereblon
C: DNA damage-binding protein 1
D: HBS1-like protein
E: Protein cereblon
F: DNA damage-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)394,05610
Polymers392,8466
Non-polymers1,2104
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, gel filtration, In presence of TNG961, proteins elute as a ternary complex
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein HBS1-like protein / ERFS


Mass: 22947.010 Da / Num. of mol.: 2 / Fragment: domain 2 + domain 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HBS1L, HBS1, KIAA1038 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q9Y450, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#2: Protein Protein cereblon


Mass: 46378.293 Da / Num. of mol.: 2
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
#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: 127097.469 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#4: Chemical ChemComp-A1C4S / N-{6-[(3R)-2,6-dioxopiperidin-3-yl]naphthalen-1-yl}-N'-{2-[6-(trifluoromethyl)-1-benzothiophen-2-yl]propan-2-yl}urea


Mass: 539.569 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H24F3N3O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestY
Has protein modificationY

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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 HBS1L, cereblon, and DDB1 with TNG961
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.393 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
Details: 0.1 M HEPES (pH 7.5), 0.24 M sodium chloride, 3 mM TCEP, 0.2 % n-octylglucoside
SpecimenConc.: 8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: sample kept at 4 degrees Celsius
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K

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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 magnification: 130000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 48 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of real images: 9532
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1RELION5particle selection
2RELION5image acquisition
4RELION5CTF correction
7PHENIX1.20.1_4487model fitting
11RELION5classification
12RELION53D reconstruction
13PHENIX1.20.1_4487model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4475226
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 669259 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL / Target criteria: cross-correlation coefficient
Details: rigid body placement of proteins followed by real space refinement
Atomic model building

3D fitting-ID: 1 / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeChain-IDInitial refinement model-IDSource nameDetails (eV)
15HXB

5hxb

B5HXBB1PDB
25HXB

5hxb

C5HXBC1PDB
3Otherproprietary HBS1L crystal structure
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 35.79 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003920527
ELECTRON MICROSCOPYf_angle_d0.543727780
ELECTRON MICROSCOPYf_chiral_restr0.04583161
ELECTRON MICROSCOPYf_plane_restr0.00393538
ELECTRON MICROSCOPYf_dihedral_angle_d14.60717648

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