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- EMDB-75840: Cryo-EM structure of CRBN in complex with HBS1L and TNG-4857 (foc... -

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Entry
Database: EMDB / ID: EMD-75840
TitleCryo-EM structure of CRBN in complex with HBS1L and TNG-4857 (focused refinement)
Map datamain map
Sample
  • Complex: Dimeric assembly of the ternary complex of CRBN/DDB1 plus HBS1L and TNG-4857
    • Complex: Dimeric assembly of CRBN + HBS1L in complex with TNG-4857 (region of focused refinement)
      • Protein or peptide: HBS1-like protein
      • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: N-[(3S)-2,6-dioxopiperidin-3-yl]-2-fluoro-3-[(2-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}propan-2-yl)carbamamido]benzamide
KeywordsFOCAD / PELO / ribosome / ubiquitin / CYTOSOLIC PROTEIN
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 / ribosome disassembly / limb development / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / translation elongation factor activity / positive regulation of Wnt signaling pathway ...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 / ribosome disassembly / limb development / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / translation elongation factor activity / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / rescue of stalled cytosolic ribosome / cytosolic ribosome / positive regulation of protein-containing complex assembly / regulation of translation / Potential therapeutics for SARS / 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 ubiquitination / translation / GTPase activity / GTP binding / perinuclear region of cytoplasm / signal transduction / extracellular exosome / 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) / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Protein cereblon / HBS1-like protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsWhittington DA
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
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
DepositionMar 5, 2026-
Header (metadata) releaseMay 6, 2026-
Map releaseMay 6, 2026-
UpdateMay 6, 2026-
Current statusMay 6, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75840.png

Downloads & links

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Map

FileDownload / File: emd_75840.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.17 Å/pix.
x 256 pix.
= 298.24 Å		1.17 Å/pix.
x 256 pix.
= 298.24 Å		1.17 Å/pix.
x 256 pix.
= 298.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.165 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.027
Minimum - Maximum-0.124320745 - 0.25156662
Average (Standard dev.)0.00014647962 (±0.0055276765)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 298.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_75840_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 1

Fileemd_75840_half_map_1.map
Annotationhalf_map_1
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_75840_half_map_2.map
Annotationhalf_map_2
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Dimeric assembly of the ternary complex of CRBN/DDB1 plus HBS1L a...

EntireName: Dimeric assembly of the ternary complex of CRBN/DDB1 plus HBS1L and TNG-4857
Components
  • Complex: Dimeric assembly of the ternary complex of CRBN/DDB1 plus HBS1L and TNG-4857
    • Complex: Dimeric assembly of CRBN + HBS1L in complex with TNG-4857 (region of focused refinement)
      • Protein or peptide: HBS1-like protein
      • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: N-[(3S)-2,6-dioxopiperidin-3-yl]-2-fluoro-3-[(2-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}propan-2-yl)carbamamido]benzamide

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Supramolecule #1: Dimeric assembly of the ternary complex of CRBN/DDB1 plus HBS1L a...

SupramoleculeName: Dimeric assembly of the ternary complex of CRBN/DDB1 plus HBS1L and TNG-4857
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: CRBN/DDB1 complex co-expressed and purified then mixed with HBS1L and TNG-4857
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 138 KDa

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Supramolecule #2: Dimeric assembly of CRBN + HBS1L in complex with TNG-4857 (region...

SupramoleculeName: Dimeric assembly of CRBN + HBS1L in complex with TNG-4857 (region of focused refinement)
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: HBS1-like protein

MacromoleculeName: HBS1-like protein / type: protein_or_peptide / ID: 1 / Details: domains 2+3 / Number of copies: 2 / 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: 22.94701 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GKPPQRSIDK PFRLCVSDVF KDQGSGFCIT GKIEAGYIQT GDRLLAMPPN ETCTVKGITL HDEPVDWAAA GDHVSLTLVG MDIIKINVG CIFCGPKVPI KACTRFRARI LIFNIEIPIT KGFPVLLHYQ TVSEPAVIKR LISVLNKSTG EVTKKKPKFL T KGQNALVE ...String:
GKPPQRSIDK PFRLCVSDVF KDQGSGFCIT GKIEAGYIQT GDRLLAMPPN ETCTVKGITL HDEPVDWAAA GDHVSLTLVG MDIIKINVG CIFCGPKVPI KACTRFRARI LIFNIEIPIT KGFPVLLHYQ TVSEPAVIKR LISVLNKSTG EVTKKKPKFL T KGQNALVE LQTQRPIALE LYKDFKELGR FMLRYGGSTI AAGVVTEIKE

UniProtKB: HBS1-like protein

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Macromolecule #2: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.378293 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GEAKKPNIIN FDTSLPTSHT YLGADMEEFH GRTLHDDDSC QVIPVLPQVM MILIPGQTLP LQLFHPQEVS MVRNLIQKDR TFAVLAYSN VQEREAQFGT TAEIYAYREE QDFGIEIVKV KAIGRQRFKV LELRTQSDGI QQAKVQILPE CVLPSTMSAV Q LESLNKCQ ...String:
GEAKKPNIIN FDTSLPTSHT YLGADMEEFH GRTLHDDDSC QVIPVLPQVM MILIPGQTLP LQLFHPQEVS MVRNLIQKDR TFAVLAYSN VQEREAQFGT TAEIYAYREE QDFGIEIVKV KAIGRQRFKV LELRTQSDGI QQAKVQILPE CVLPSTMSAV Q LESLNKCQ IFPSKPVSRE DQCSYKWWQK YQKRKFHCAN LTSWPRWLYS LYDAETLMDR IKKQLREWDE NLKDDSLPSN PI DFSYRVA ACLPIDDVLR IQLLKIGSAI QRLRCELDIM NKCTSLCCKQ CQETEITTKN EIFSLSLCGP MAAYVNPHGY VHE TLTVYK ACNLNLIGRP STEHSWFPGY AWTVAQCKIC ASHIGWKFTA TKKDMSPQKF WGLTRSALLP TIPDTEDEIS PDKV ILCL

UniProtKB: Protein cereblon

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: N-[(3S)-2,6-dioxopiperidin-3-yl]-2-fluoro-3-[(2-{4-[1-(trifluorom...

MacromoleculeName: N-[(3S)-2,6-dioxopiperidin-3-yl]-2-fluoro-3-[(2-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}propan-2-yl)carbamamido]benzamide
type: ligand / ID: 4 / Number of copies: 2 / Formula: A1C9W
Molecular weightTheoretical: 534.503 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

Concentration8 mg/mL
BufferpH: 7.5 / Details: 10 mM HEPES (pH 7.5), 240 mM NaCl, 3 mM TCEP
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 48.0 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: 1.0 µm / Nominal magnification: 130000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 10420085
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5hxb


Details: And proprietary crystal structure of HBS1L
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 661458
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 4

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Atomic model buiding 1

Initial model
PDB IDChainDetails

5hxb

chain_id: A, source_name: PDB, initial_model_type: experimental model
chain_id: B, source_name: Other, initial_model_type: experimental modelproprietary crystal structure of HBS1L
RefinementSpace: REAL / Protocol: RIGID BODY FIT / Target criteria: cross-correlation coefficent
Output model

PDB-11mr:
Cryo-EM structure of CRBN in complex with HBS1L and TNG-4857 (focused refinement)

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