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- PDB-11mr: Cryo-EM structure of CRBN in complex with HBS1L and TNG-4857 (foc... -

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Basic information

Entry
Database: PDB / ID: 11mr
TitleCryo-EM structure of CRBN in complex with HBS1L and TNG-4857 (focused refinement)
Components
  • HBS1-like protein
  • Protein cereblon
KeywordsCYTOSOLIC PROTEIN / FOCAD / PELO / ribosome / 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 / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsWhittington, D.A.
Funding support United States, 1items
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, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 6, 2026Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: HBS1-like protein
B: Protein cereblon
C: HBS1-like protein
D: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,8508
Polymers138,6514
Non-polymers1,2004
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 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
Details: domains 2+3 / 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: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-A1C9W / N-[(3S)-2,6-dioxopiperidin-3-yl]-2-fluoro-3-[(2-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}propan-2-yl)carbamamido]benzamide


Mass: 534.503 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H26F4N4O4 / 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

Component
IDNameTypeDetails (eV)Entity IDParent-IDSource
1Dimeric assembly of the ternary complex of CRBN/DDB1 plus HBS1L and TNG-4857COMPLEXCRBN/DDB1 complex co-expressed and purified then mixed with HBS1L and TNG-4857#1-#20RECOMBINANT
2Dimeric assembly of CRBN + HBS1L in complex with TNG-4857 (region of focused refinement)COMPLEX#1-#21RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.393 MDaNO
210.138 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Spodoptera frugiperda (fall armyworm)7108
32Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.5 / Details: 10 mM HEPES (pH 7.5), 240 mM NaCl, 3 mM TCEP
SpecimenConc.: 8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE

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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: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 48 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION5particle selection
2RELION5image acquisition
7PHENIX1.20.1_4487model fitting
12RELION53D reconstruction
13PHENIX1.20.1_4487model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 10420085
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 661458 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL / Target criteria: cross-correlation coefficent
Atomic model building

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

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

5hxb

A5HXBA1PDB
2BB2Otherproprietary crystal structure of HBS1L
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 63.61 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00387968
ELECTRON MICROSCOPYf_angle_d0.548310808
ELECTRON MICROSCOPYf_chiral_restr0.04241224
ELECTRON MICROSCOPYf_plane_restr0.00451356
ELECTRON MICROSCOPYf_dihedral_angle_d5.99131054

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