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- PDB-9gy3: Crystal structure of CRBNmidi in complex with (S)-dHTC1 -

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Basic information

Entry
Database: PDB / ID: 9gy3
TitleCrystal structure of CRBNmidi in complex with (S)-dHTC1
ComponentsProtein cereblon
KeywordsLIGASE / E3 Ligase / TPD / molecular glue / induced proximity
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / positive regulation of protein-containing complex assembly / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / protein ubiquitination ...negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / positive regulation of protein-containing complex assembly / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / protein ubiquitination / perinuclear region of cytoplasm / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
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) / PUA-like superfamily
Similarity search - Domain/homology
: / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsRutter, Z.J. / Shaum, J.B. / Ciulli, A. / Erb, M.A.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: bioRxiv / Year: 2025
Title: High-throughput diversification of protein-ligand surfaces to discover chemical inducers of proximity.
Authors: James B Shaum / Miquel Muñoz I Ordoño / Erica A Steen / Daniela V Wenge / Hakyung Cheong / Moritz Hunkeler / Eric M Bilotta / Zoe Rutter / Paige A Barta / Abby M Thornhill / Natalia ...Authors: James B Shaum / Miquel Muñoz I Ordoño / Erica A Steen / Daniela V Wenge / Hakyung Cheong / Moritz Hunkeler / Eric M Bilotta / Zoe Rutter / Paige A Barta / Abby M Thornhill / Natalia Milosevich / Lauren M Hargis / Jordan Janowski / Timothy R Bishop / Trever R Carter / Bryce da Camara / Matthias Hinterndorfer / Lucas Dada / Wen-Ji He / Fabian Offensperger / Hirotake Furihata / Sydney R Schweber / Charlie Hatton / Yanhe Wen / Benjamin F Cravatt / Keary M Engle / Katherine A Donovan / Bruno Melillo / Seiya Kitamura / Alessio Ciulli / Scott A Armstrong / Eric S Fischer / Georg E Winter / Michael A Erb
Abstract: Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of ...Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of heterobifunctional CIPs, monovalent, molecular glue-like CIPs have relied predominantly on serendipity. Envisioning a prospective approach to discover molecular glues for a pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications to empirically discover protein-ligand surfaces that are tuned to cooperatively engage another protein interface. Here, we used sulfur(VI)-fluoride exchange (SuFEx)-based high-throughput chemistry (HTC) to install 3,163 structurally diverse chemical building blocks onto ENL and BRD4 ligands and then screened the crude products for degrader activity. This revealed dHTC1, a potent, selective, and stereochemistry-dependent degrader of ENL. It recruits CRL4 to ENL through an extended interface of protein-protein and protein-ligand contacts, but only after pre-forming the ENL:dHTC1 complex. We also characterized two structurally distinct BRD4 degraders, including dHTC3, a molecular glue that selectively dimerizes the first bromodomain of BRD4 to SCF , an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and actionable cellular effectors of proximity pharmacology.
History
DepositionOct 1, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 1, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein cereblon
C: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4426
Polymers74,9582
Non-polymers1,4844
Water1,20767
1
A: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2213
Polymers37,4791
Non-polymers7422
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2213
Polymers37,4791
Non-polymers7422
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.501, 53.501, 236.121
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31
Space group name HallP31
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3

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Components

#1: Protein Protein cereblon


Mass: 37478.805 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: Escherichia coli (E. coli) / References: UniProt: Q96SW2
#2: Chemical ChemComp-A1IQT / 2-[3-[2-[4-[[(5~{S})-1,3-bis(oxidanylidene)-2,7-diazaspiro[4.4]nonan-7-yl]sulfonylamino]piperidin-1-yl]ethylcarbamoyl]phenyl]-~{N}-cyclobutyl-imidazo[1,2-a]pyridine-6-carboxamide


Mass: 676.786 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H40N8O6S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 67 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.6 Å3/Da / Density % sol: 52.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Morpheus H10 (0.1 M Buffer System 3 pH 8.5, 0.12 M Alcohols, 30 % Precipitant Mix 2) (Molecular Dimensions)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.6199 Å
DetectorType: DECTRIS EIGER2 X CdTe 9M / Detector: PIXEL / Date: May 20, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.6199 Å / Relative weight: 1
ReflectionResolution: 2.5→236.12 Å / Num. obs: 26206 / % possible obs: 98.3 % / Redundancy: 10.7 % / Biso Wilson estimate: 51.55 Å2 / CC1/2: 0.969 / Net I/σ(I): 3.5
Reflection shellResolution: 2.5→2.6 Å / Num. unique obs: 2917 / CC1/2: 0.182

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158-000refinement
DIALSdata reduction
DIALSdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→43.13 Å / SU ML: 0.4675 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 36.037
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3032 1238 4.82 %
Rwork0.2437 24452 -
obs0.2465 25690 98.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 56.77 Å2
Refinement stepCycle: LAST / Resolution: 2.5→43.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5075 0 98 67 5240
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00245293
X-RAY DIFFRACTIONf_angle_d0.56457198
X-RAY DIFFRACTIONf_chiral_restr0.0433804
X-RAY DIFFRACTIONf_plane_restr0.0042923
X-RAY DIFFRACTIONf_dihedral_angle_d8.2082748
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.60.3907800.37772494X-RAY DIFFRACTION89.75
2.6-2.720.35271510.36252683X-RAY DIFFRACTION96.04
2.72-2.860.36891500.32192709X-RAY DIFFRACTION99.76
2.86-3.040.40261180.34132776X-RAY DIFFRACTION99.86
3.04-3.280.36621300.29812798X-RAY DIFFRACTION99.93
3.28-3.60.32531660.23582738X-RAY DIFFRACTION100
3.61-4.130.29441720.2312736X-RAY DIFFRACTION100
4.13-5.20.24851460.18832763X-RAY DIFFRACTION99.97
5.2-43.130.25591250.19312755X-RAY DIFFRACTION99.17

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