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- PDB-29hh: Cryo-EM structure of the CUL1-RBX1-SKP1-FBXO22 SCF ubiquition lig... -

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Entry
Database: PDB / ID: 29hh
TitleCryo-EM structure of the CUL1-RBX1-SKP1-FBXO22 SCF ubiquition ligase in complex with NSD2, UNC10088 and Bach1
Components
  • Cullin-1
  • E3 ubiquitin-protein ligase RBX1
  • F-box only protein 22
  • Histone-lysine N-methyltransferase NSD2
  • S-phase kinase-associated protein 1
  • Transcription regulator protein BACH1
KeywordsLIGASE / Ubiquitin Ligase / Targeted protein degradation / cullin-RING ligase / SKP1 CUL1 F box SCF / Nuclear receptor binding SET domain-containing 2 NSD2
Function / homology
Function and homology information


[histone H3]-lysine36 N-dimethyltransferase / Regulation of HMOX1 expression and activity / regulation of skeletal muscle fiber development / histone H4K20 methyltransferase activity / histone H3K36 dimethyltransferase activity / regulation of xenophagy / Parkin-FBXW7-Cul1 ubiquitin ligase complex / histone H3K36 trimethyltransferase activity / F-box domain binding / synaptic assembly at neuromuscular junction ...[histone H3]-lysine36 N-dimethyltransferase / Regulation of HMOX1 expression and activity / regulation of skeletal muscle fiber development / histone H4K20 methyltransferase activity / histone H3K36 dimethyltransferase activity / regulation of xenophagy / Parkin-FBXW7-Cul1 ubiquitin ligase complex / histone H3K36 trimethyltransferase activity / F-box domain binding / synaptic assembly at neuromuscular junction / regulation of cell cycle process / neural crest cell differentiation / ligand-modulated transcription factor activity / histone H3K36 methyltransferase activity / regulation of BMP signaling pathway / PcG protein complex / negative regulation of beige fat cell differentiation / regulation of mitophagy / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / regulation of centrosome duplication / cullin-RING ubiquitin ligase complex / maintenance of protein location in nucleus / Cul7-RING ubiquitin ligase complex / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / cellular response to chemical stress / regulation of TOR signaling / positive regulation of protein autoubiquitination / RNA polymerase II transcription initiation surveillance / protein neddylation / ubiquitin ligase activator activity / regulation of DNA damage checkpoint / NEDD8 ligase activity / nucleocytoplasmic transport / NFE2L2 regulating anti-oxidant/detoxification enzymes / negative regulation of response to oxidative stress / protein K27-linked ubiquitination / histone H3 methyltransferase activity / VCB complex / Cul5-RING ubiquitin ligase complex / ubiquitin-ubiquitin ligase activity / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / Cul3-RING ubiquitin ligase complex / negative regulation of type I interferon production / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / negative regulation of mitophagy / Prolactin receptor signaling / limb development / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / centrosome duplication / cilium assembly / protein monoubiquitination / cullin family protein binding / GSK3B-mediated proteasomal degradation of PD-L1(CD274) / ubiquitin-like ligase-substrate adaptor activity / signal transduction in response to DNA damage / Nuclear events stimulated by ALK signaling in cancer / protein K48-linked ubiquitination / negative regulation of insulin receptor signaling pathway / regulation of cellular response to insulin stimulus / positive regulation of TORC1 signaling / animal organ morphogenesis / intrinsic apoptotic signaling pathway / transcription-coupled nucleotide-excision repair / post-translational protein modification / regulation of mitotic cell cycle / cellular response to starvation / molecular function activator activity / protein modification process / negative regulation of canonical NF-kappaB signal transduction / cellular response to amino acid stimulus / site of DNA damage / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / T cell activation / Heme signaling / G1/S transition of mitotic cell cycle / negative regulation of canonical Wnt signaling pathway / Nonhomologous End-Joining (NHEJ) / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / Vpu mediated degradation of CD4 / Dectin-1 mediated noncanonical NF-kB signaling / Degradation of DVL / cell population proliferation / Degradation of CRY and PER proteins / Activation of NF-kappaB in B cells / Iron uptake and transport / Degradation of GLI1 by the proteasome / Recognition of DNA damage by PCNA-containing replication complex / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Negative regulation of NOTCH4 signaling / RING-type E3 ubiquitin transferase / regulation of circadian rhythm / Hedgehog 'on' state
Similarity search - Function
FIST, C-domain / FIST C domain / FIST_C / BACH, basic leucine zipper (bZIP) domain / : / : / : / : / : / : ...FIST, C-domain / FIST C domain / FIST_C / BACH, basic leucine zipper (bZIP) domain / : / : / : / : / : / : / : / : / F-box domain / Basic leucine zipper domain, Maf-type / bZIP Maf transcription factor / NSD, Cys-His rich domain / : / : / : / NSD Cys-His rich domain / Histone-lysine N-methyltransferase NSD-like, PHD zinc finger / Histone-lysine N-methyltransferase NSD-like, variant PHD zinc finger / Histone-lysine N-methyltransferase NSD-like, PHD zinc finger 1 / Transcription factor, Skn-1-like, DNA-binding domain superfamily / : / : / AWS domain / AWS domain / AWS domain profile. / associated with SET domains / F-box-like domain superfamily / SKP1 component, dimerisation / S-phase kinase-associated protein 1 / SKP1-like, dimerisation domain superfamily / Skp1 family, dimerisation domain / F-box domain / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Cysteine-rich motif following a subset of SET domains / Basic-leucine zipper (bZIP) domain signature. / : / Cullin protein neddylation domain / Basic-leucine zipper (bZIP) domain profile. / basic region leucin zipper / Cullin, conserved site / Cullin family signature. / Cullin, N-terminal / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Post-SET domain / Post-SET domain profile. / Basic-leucine zipper domain / Cullin alpha solenoid domain / Basic-leucine zipper domain superfamily / HMG (high mobility group) box / Cullin / : / Cullin alpha+beta domain / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / HMG boxes A and B DNA-binding domains profile. / high mobility group / High mobility group box domain / High mobility group box domain superfamily / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain profile. / SET domain superfamily / SET domain / BTB/POZ domain / BTB domain profile. / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / Zinc finger, PHD-type, conserved site / PHD-finger / Zinc finger PHD-type signature. / SKP1/BTB/POZ domain superfamily / Ring finger / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Zinc finger RING-type profile. / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
: / Transcription regulator protein BACH1 / Histone-lysine N-methyltransferase NSD2 / E3 ubiquitin-protein ligase RBX1 / S-phase kinase-associated protein 1 / Cullin-1 / F-box only protein 22
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsAmann, S.J. / Robertson, K.C. / Grishkovskaya, I. / Liu, T. / James, L.I. / Brown, N.B. / Haselbach, D.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA242305 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35GM128855 United States
Citation
Journal: Nat Commun / Year: 2026
Title: Structural basis of NSD2 degradation via targeted recruitment of SCF-FBXO22.
Authors: Kevin C Robertson / Sascha J Amann / Tongkun Liu / Adam V Funk / Xianxi Wang / Irina Grishkovskaya / Aamir Mehmood / John R Tabor / Jacqueline L Norris-Drouin / Cheryl H Arrowsmith / Jon L ...Authors: Kevin C Robertson / Sascha J Amann / Tongkun Liu / Adam V Funk / Xianxi Wang / Irina Grishkovskaya / Aamir Mehmood / John R Tabor / Jacqueline L Norris-Drouin / Cheryl H Arrowsmith / Jon L Collins / Yinglong Miao / Michael J Emanuele / David Haselbach / Lindsey I James / Nicholas G Brown /
Abstract: Targeted protein degradation (TPD) through the ubiquitin-proteasome system is driven by compound-mediated polyubiquitination of a protein-of-interest by an E3 ubiquitin (Ub) ligase. Relatively few ...Targeted protein degradation (TPD) through the ubiquitin-proteasome system is driven by compound-mediated polyubiquitination of a protein-of-interest by an E3 ubiquitin (Ub) ligase. Relatively few E3s have been successfully utilized for TPD and the governing principles of functional ternary complex formation between the E3, degrader, and protein target remain elusive. FBXO22 has recently been harnessed for TPD applications by degraders that covalently modify its cysteine residues. Here, we reveal that the aldehyde derivative of UNC10088 promotes cooperative binding of FBXO22 to NSD2, a histone methyltransferase and oncogenic protein, leading to a cryo-EM structure of the SKP1-CUL1-F-box (SCF)-FBXO22 complex with NSD2. This structure revealed a conformational change in the FBXO22 loop surrounding C326, further exposing the cysteine for covalent recruitment. Additional medicinal chemistry efforts led to the discovery of benzaldehyde-based non-prodrug degraders that similarly engage C326 of FBXO22 and potently degrade NSD2. Unlike many degraders, our molecules recruit NSD2 to a different surface of FBXO22 than the known FBXO22 substrate BACH1, allowing for concurrent complex formation and structural determination of SCF bound to both the neosubstrate NSD2 and native substrate BACH1. Overall, we demonstrate the biochemical and structural basis for NSD2 degradation, revealing key principles for efficient and selective TPD by SCF.
#1: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionMar 11, 2026Deposition site: PDBE / Processing site: PDBE
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: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 8, 2026Group: Data collection / Database references / Category: citation / em_admin / Item: _citation.journal_volume / _em_admin.last_update
Revision 1.1Jul 8, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin / Data content type: EM metadata / EM metadata / Item: _citation.journal_volume / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: F-box only protein 22
B: Histone-lysine N-methyltransferase NSD2
C: S-phase kinase-associated protein 1
D: Cullin-1
E: E3 ubiquitin-protein ligase RBX1
G: Transcription regulator protein BACH1
H: Transcription regulator protein BACH1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)482,5628
Polymers481,9537
Non-polymers6091
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

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Protein , 6 types, 7 molecules ABCDEGH

#1: Protein F-box only protein 22 / F-box protein FBX22p44


Mass: 44562.270 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FBXO22, FBX22 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8NEZ5
#2: Protein Histone-lysine N-methyltransferase NSD2 / Multiple myeloma SET domain-containing protein / MMSET / Nuclear SET domain-containing protein 2 / ...Multiple myeloma SET domain-containing protein / MMSET / Nuclear SET domain-containing protein 2 / Protein trithorax-5 / Wolf-Hirschhorn syndrome candidate 1 protein


Mass: 152515.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NSD2, KIAA1090, MMSET, TRX5, WHSC1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: O96028, [histone H3]-lysine36 N-dimethyltransferase
#3: Protein S-phase kinase-associated protein 1 / Cyclin-A/CDK2-associated protein p19 / p19A / Organ of Corti protein 2 / OCP-2 / Organ of Corti ...Cyclin-A/CDK2-associated protein p19 / p19A / Organ of Corti protein 2 / OCP-2 / Organ of Corti protein II / OCP-II / RNA polymerase II elongation factor-like protein / SIII / Transcription elongation factor B polypeptide 1-like / p19skp1


Mass: 18679.965 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SKP1, EMC19, OCP2, SKP1A, TCEB1L / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63208
#4: Protein Cullin-1 / CUL-1


Mass: 89800.367 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q13616
#5: Protein E3 ubiquitin-protein ligase RBX1 / E3 ubiquitin-protein transferase RBX1 / Protein ZYP / RING finger protein 75 / RING-box protein 1 / ...E3 ubiquitin-protein transferase RBX1 / Protein ZYP / RING finger protein 75 / RING-box protein 1 / Rbx1 / Regulator of cullins 1 / ROC1


Mass: 12289.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBX1, RNF75, ROC1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P62877, RING-type E3 ubiquitin transferase, cullin-RING-type E3 NEDD8 transferase
#6: Protein Transcription regulator protein BACH1 / BTB and CNC homolog 1 / HA2303


Mass: 82052.586 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACH1 / Production host: Escherichia coli (E. coli) / References: UniProt: O14867

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Non-polymers , 1 types, 1 molecules

#7: Chemical ChemComp-A1J20 / ~{N}-cyclopropyl-~{N}-[[4-[[2-(6-oxidanylhexanoyl)-1~{H}-isoquinolin-6-yl]carbamoyl]phenyl]methyl]-3-oxidanylidene-4~{H}-1,4-benzoxazine-7-carboxamide


Mass: 608.684 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H36N4O6 / Feature type: SUBJECT OF INVESTIGATION

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Details

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: SCF FBXO22, NSD2, UNC10088 / Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPES1
2200 mMSodium ChlorideNaCl1
31 mMDTT1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 75 % / Chamber temperature: 277 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 defocus max: 2000 nm / Nominal defocus min: 1000 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
9PHENIXmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 73358 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model

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