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- PDB-9rsc: Ternary complex of an improved charged molecular glue degrader ZZ... -

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Basic information

Entry
Database: PDB / ID: 9rsc
TitleTernary complex of an improved charged molecular glue degrader ZZ2-SO2H, BRD4(BD1) neosubstrate, and the CTLH E3 ligase receptor module YPEL5-WDR26
Components
  • Bromodomain-containing protein 4
  • Protein yippee-like 5
  • WD repeat-containing protein 26
KeywordsLIGASE / E3 ubiquitin ligase / CTLH / GID / YPEL5 / Molecular Glue Degrader / Targeted Protein Degradation
Function / homology
Function and homology information


GID complex / mitotic spindle pole / histone H4K8ac reader activity / RNA polymerase II C-terminal domain binding / histone H3K27ac reader activity / P-TEFb complex binding / histone H3K9ac reader activity / negative regulation of DNA damage checkpoint / histone H4 reader activity / histone H4K5ac reader activity ...GID complex / mitotic spindle pole / histone H4K8ac reader activity / RNA polymerase II C-terminal domain binding / histone H3K27ac reader activity / P-TEFb complex binding / histone H3K9ac reader activity / negative regulation of DNA damage checkpoint / histone H4 reader activity / histone H4K5ac reader activity / histone H4K12ac reader activity / host-mediated suppression of viral transcription / histone H4K16ac reader activity / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / ubiquitin ligase complex / RNA polymerase II CTD heptapeptide repeat kinase activity / Regulation of pyruvate metabolism / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / tertiary granule lumen / chromosome / regulation of inflammatory response / midbody / histone binding / Potential therapeutics for SARS / ficolin-1-rich granule lumen / proteasome-mediated ubiquitin-dependent protein catabolic process / positive regulation of canonical NF-kappaB signal transduction / transcription coactivator activity / cell population proliferation / transcription cis-regulatory region binding / chromatin remodeling / protein serine/threonine kinase activity / chromatin binding / DNA damage response / Neutrophil degranulation / regulation of transcription by RNA polymerase II / centrosome / positive regulation of DNA-templated transcription / chromatin / enzyme binding / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular region / nucleoplasm / metal ion binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Yippee domain / Yippee family / Yippee domain profile. / : / : / LisH-like dimerisation domain / C-terminal to LisH motif. / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / Yippee/Mis18/Cereblon ...Yippee domain / Yippee family / Yippee domain profile. / : / : / LisH-like dimerisation domain / C-terminal to LisH motif. / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
: / Bromodomain-containing protein 4 / Protein yippee-like 5 / WD repeat-containing protein 26
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.42 Å
AuthorsChrustowicz, J. / Schulman, B.A.
Funding support Germany, European Union, 3items
OrganizationGrant numberCountry
German Research Foundation (DFG)SCHU 3196/1-1 Germany
European Research Council (ERC)UPSmeetMet, 101098161European Union
Max Planck Society Germany
CitationJournal: Nat Chem Biol / Year: 2026
Title: Charged molecular glue discovery enabled by targeted degron display.
Authors: Zhe Zhuang / Woong Sub Byun / Jakub Chrustowicz / Zuzanna Kozicka / Veronica L Li / Dinah M Abeja / Katherine A Donovan / Sara Sepic / Inchul You / Mikołaj Słabicki / Eric S Fischer / ...Authors: Zhe Zhuang / Woong Sub Byun / Jakub Chrustowicz / Zuzanna Kozicka / Veronica L Li / Dinah M Abeja / Katherine A Donovan / Sara Sepic / Inchul You / Mikołaj Słabicki / Eric S Fischer / Stephen M Hinshaw / Benjamin L Ebert / Brenda A Schulman / Nathanael S Gray /
Abstract: Small molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways and tools for agriculture. Explosive growth of targeted protein degradation ...Small molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways and tools for agriculture. Explosive growth of targeted protein degradation drug development has spurred renewed interest in proximity-inducing molecules, especially molecular glue degraders (MGDs). These compounds catalyze the destruction of disease-causing proteins by reshaping protein surfaces and promoting cooperative binding between ubiquitylating enzymes and target proteins. MGD discovery for predefined targets is a major challenge in contemporary drug discovery. Here, we solve this important chemical challenge through 'chemocentric' MGD discovery of ZZ1, a BET-family protein degrader and a prodrug of a negatively charged glue. ZZ1 activation unmasks a sulfinic acid that binds the modular CTLH ubiquitin ligase complex through a basic pocket in its YPEL5 subunit. These findings demonstrate a previously unrecognized capacity of YPEL5 to recruit CTLH substrates and enable the discovery of MGDs for exceedingly common acidic and basic degrons.
History
DepositionJul 1, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 8, 2026Provider: repository / Type: Initial release
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Revision 1.0Apr 8, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
7: WD repeat-containing protein 26
W: WD repeat-containing protein 26
Y: Protein yippee-like 5
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)171,0378
Polymers170,1674
Non-polymers8714
Water362
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 , 3 types, 4 molecules 7WYB

#1: Protein WD repeat-containing protein 26 / CUL4- and DDB1-associated WDR protein 2 / Myocardial ischemic preconditioning up-regulated protein 2


Mass: 70539.773 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR26, CDW2, MIP2, PRO0852 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9H7D7
#2: Protein Protein yippee-like 5


Mass: 13860.658 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YPEL5, CGI-127 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62699
#3: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 15226.416 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The first bromodomain (BD1) of BRD4. The GGSGS sequence is a linker between BD1 and the upstream TEV cleavage site.
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885

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Non-polymers , 3 types, 6 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-A1IL8 / 2,6-bis(chloranyl)-4-[[4-[(9S)-4,5,13-trimethyl-9-[2-[(2-methylpropan-2-yl)oxy]-2-oxidanylidene-ethyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]carbamoyl]benzenesulfinic acid


Mass: 674.618 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H29Cl2N5O5S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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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: ZZ2-SO2H-induced complex between YPEL5-CTLH E3 ligase and the first bromodomain (BD1) of BRD4
Type: COMPLEX
Details: The YPEL5-CTLH complex consists of TWA1, RANBP9, RMND5A, MAEA, WDR26, and YPEL5.
Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 1 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
SpecimenConc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Sample mixed with 0.1% beta-OG right before plunging
VitrificationCryogen name: NITROGEN

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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: 2300 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 63.6 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1Gautomatchparticle selection
2PHENIX1.21.1_5286model refinement
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 5422892
3D reconstructionResolution: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 24545 / Symmetry type: POINT
Atomic model buildingPDB-ID: 9GHQ

9ghq
PDB Unreleased entry


Accession code: 9GHQ / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3.42 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037744
ELECTRON MICROSCOPYf_angle_d0.54510557
ELECTRON MICROSCOPYf_dihedral_angle_d4.4971068
ELECTRON MICROSCOPYf_chiral_restr0.0441187
ELECTRON MICROSCOPYf_plane_restr0.0031361

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