[English] 日本語
Yorodumi
- EMDB-75840: Cryo-EM structure of CRBN in complex with HBS1L and TNG-4857 (foc... -

+
Open data


ID or keywords:

Loading...

-
Basic information

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 / locomotory exploration behavior / Cul4A-RING E3 ubiquitin ligase complex / limb development / PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA / 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 / locomotory exploration behavior / Cul4A-RING E3 ubiquitin ligase complex / limb development / PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / rescue of stalled cytosolic ribosome / positive regulation of protein-containing complex assembly / cytosolic ribosome / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / transmembrane transporter binding / protein ubiquitination / translation / GTPase activity / GTP binding / perinuclear region of cytoplasm / signal transduction / metal ion binding / extracellular exosome / membrane / nucleus / cytosol / cytoplasm
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 W 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, the deletion of adjacent genes can generate therapeutic vulnerabilities. MTAP is frequently co-deleted with the chr9p21 tumor ...When tumor suppressor genes are lost through chromosomal deletion, the deletion of adjacent genes can generate therapeutic vulnerabilities. MTAP is frequently co-deleted with the chr9p21 tumor suppressor gene CDKN2A, creating a synthetic lethal dependency on protein arginine methyltransferase 5 (PRMT5). Telomeric to MTAP lies focadhesin (FOCAD), whose loss induces dependency on the HBS1-like translational GTPase (HBS1L)-protein pelota homolog (PELO) ribosome rescue complex for translational maintenance. FOCAD is deleted in ∼1 out of 3 MTAP-deleted cancers. We screened an immunomodulatory imide drug (IMiD)-focused diversity library and identified a weak hit that bound cereblon (CRBN), 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 the clinical evaluation of TNG961 as a first-in-class precision oncology therapeutic.
SIGNIFICANCE: FOCAD deletion, frequently co-occurring with MTAP/CDKN2A loss, creates a synthetic lethal dependency on the HBS1L-PELO ribosome rescue complex. TNG961, a first-in-class molecular glue ...SIGNIFICANCE: FOCAD deletion, frequently co-occurring with MTAP/CDKN2A loss, creates a synthetic lethal dependency on the HBS1L-PELO ribosome rescue complex. TNG961, a first-in-class molecular glue degrader of HBS1L, enforces translational arrest and drives tumor regressions in FOCAD-negative models, including PRMT5 inhibitor-refractory tumors, establishing a novel precision oncology strategy for chromosome 9p21 co-deletion contexts.
History
DepositionMar 5, 2026-
Header (metadata) releaseMay 6, 2026-
Map releaseMay 6, 2026-
UpdateSep 16, 2026-
Current statusSep 16, 2026Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_75840.png

Downloads & links

-
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 °

-
Supplemental data

-
Mask #1

Fileemd_75840_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: half map 1

Fileemd_75840_half_map_1.map
Annotationhalf_map_1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: half map 2

Fileemd_75840_half_map_2.map
Annotationhalf_map_2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
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

-
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

-
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)

-
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

-
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

-
Macromolecule #3: ZINC ION

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

-
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

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
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

-
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

+
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

-
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)

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more