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- PDB-8rq9: Crystal structure of PROTAC CFT-1297 in complex with CRBN-midi an... -

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Basic information

Entry
Database: PDB / ID: 8rq9
TitleCrystal structure of PROTAC CFT-1297 in complex with CRBN-midi and BRD4(BD2)
Components
  • Bromodomain-containing protein 4
  • Protein cereblon
KeywordsLIGASE / E3 ligase / PROTAC / TPD / targeted protein degradation
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / RNA polymerase II C-terminal domain binding / P-TEFb complex binding / locomotory exploration behavior / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of Wnt signaling pathway ...negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / RNA polymerase II C-terminal domain binding / P-TEFb complex binding / locomotory exploration behavior / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of Wnt signaling pathway / positive regulation of T-helper 17 cell lineage commitment / negative regulation of protein-containing complex assembly / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / positive regulation of protein-containing complex assembly / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / transcription coactivator activity / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / protein ubiquitination / chromatin remodeling / protein serine/threonine kinase activity / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / 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 ...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 / 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
Similarity search - Domain/homology
: / Bromodomain-containing protein 4 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.91 Å
AuthorsDarren, D. / Ramachandran, S. / Kroupova, A. / Zollman, D. / Ciulli, A.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Nat Commun / Year: 2024
Title: Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders.
Authors: Kroupova, A. / Spiteri, V.A. / Rutter, Z.J. / Furihata, H. / Darren, D. / Ramachandran, S. / Chakraborti, S. / Haubrich, K. / Pethe, J. / Gonzales, D. / Wijaya, A.J. / Rodriguez-Rios, M. / ...Authors: Kroupova, A. / Spiteri, V.A. / Rutter, Z.J. / Furihata, H. / Darren, D. / Ramachandran, S. / Chakraborti, S. / Haubrich, K. / Pethe, J. / Gonzales, D. / Wijaya, A.J. / Rodriguez-Rios, M. / Sturbaut, M. / Lynch, D.M. / Farnaby, W. / Nakasone, M.A. / Zollman, D. / Ciulli, A.
History
DepositionJan 17, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 25, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Advisory / Database references ...Advisory / Database references / Refinement description / Structure summary
Category: citation / citation_author ...citation / citation_author / entity / pdbx_entry_details / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_residues / struct_ncs_dom_lim / struct_ref_seq_dif
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _entity.details / _pdbx_entry_details.has_protein_modification / _pdbx_poly_seq_scheme.pdb_seq_num / _pdbx_unobs_or_zero_occ_residues.auth_seq_id / _struct_ref_seq_dif.pdbx_auth_seq_num

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein cereblon
B: Bromodomain-containing protein 4
D: Bromodomain-containing protein 4
C: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,8588
Polymers105,0784
Non-polymers1,7804
Water55831
1
A: Protein cereblon
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4294
Polymers52,5392
Non-polymers8902
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Bromodomain-containing protein 4
C: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4294
Polymers52,5392
Non-polymers8902
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.882, 52.638, 130.348
Angle α, β, γ (deg.)96.440, 91.490, 99.220
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 48 through 67 or (resid 68...
d_2ens_1(chain "C" and (resid 48 through 49 or (resid 50...
d_1ens_2(chain "B" and (resid 337 through 360 or (resid 361...
d_2ens_2(chain "D" and (resid 337 through 351 or (resid 352...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1ASNASNTHRTHRAA48 - 4259 - 328
d_12ens_1A1H2FA1H2FA1H2FA1H2FAE501
d_21ens_1ASNASNTHRTHRCD48 - 4259 - 328
d_22ens_1A1H2FA1H2FA1H2FA1H2FCG501
d_11ens_2ASPASPALAALABB337 - 3667 - 36
d_12ens_2ALAALAPROPROBB371 - 45841 - 128
d_21ens_2ASPASPALAALADC337 - 3667 - 36
d_22ens_2ALAALAPROPRODC371 - 45841 - 128

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(0.873575259065, 0.290140845234, -0.390748712955), (0.289133161875, -0.955221676971, -0.0628773611737), (-0.39149493158, -0.0580503037986, -0.918347363897)30.5260364702, -72.9957360093, 77.6105431387
2given(0.999857519253, 0.00818773398686, 0.0147615109244), (0.00828444358171, -0.999944542719, -0.00650226735637), (0.0147074534558, 0.0066236318129, -0.999869900694)10.8536022302, -70.8490180491, 72.9227048528

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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
Details: Compared to the WT protein, our construct is lacking residues 188 - 248 (WT numbering) which are substituted by Gly188-Ser189-Gly190. Plus the following mutations were introduced: C78I, ...Details: Compared to the WT protein, our construct is lacking residues 188 - 248 (WT numbering) which are substituted by Gly188-Ser189-Gly190. Plus the following mutations were introduced: C78I, I92V, K116N, Q134E, R283W, C287N, V293S,G302D, L342R, C343E, T359I, L423I.,Compared to the WT protein, our construct is lacking residues 188 - 248 (WT numbering) which are substituted by Gly188-Ser189-Gly190. Plus the following mutations were introduced: C78I, I92V, K116N, Q134E, R283W, C287N, V293S,G302D, L342R, C343E, T359I, L423I.
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Production host: Escherichia coli (E. coli) / References: UniProt: Q96SW2
#2: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 15060.332 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#3: Chemical ChemComp-A1H2F / (3~{S})-3-[7-[1-[7-[4-[6-(4-chlorophenyl)-1-methyl-spiro[[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4,1'-cyclopropane]-8-yl]pyrazol-1-yl]heptyl]piperidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]piperidine-2,6-dione


Mass: 824.411 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C47H50ClN9O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


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


Mass: 18.015 Da / Num. of mol.: 31 / 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: 2.81 Å3/Da / Density % sol: 50.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% (w/v) PEG 3350, 0.2 M sodium citrate and 0.1 M Bis-Tris Propane pH 7.5

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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 EIGER X 9M / Detector: PIXEL / Date: Jul 24, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.6199 Å / Relative weight: 1
ReflectionResolution: 2.91→46.1 Å / Num. obs: 20285 / % possible obs: 97.8 % / Redundancy: 6.6 % / CC1/2: 0.99 / Net I/σ(I): 3.3
Reflection shellResolution: 2.91→2.96 Å / Redundancy: 6 % / Num. unique obs: 275 / CC1/2: 0.26 / % possible all: 75.6

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
xia2data reduction
xia2.multiplexdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.91→43.27 Å / SU ML: 0.5272 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 37.6085
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2926 1620 7.99 %
Rwork0.2488 18665 -
obs0.2524 20285 80.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 74.17 Å2
Refinement stepCycle: LAST / Resolution: 2.91→43.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6231 0 122 31 6384
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00616512
X-RAY DIFFRACTIONf_angle_d0.89518934
X-RAY DIFFRACTIONf_chiral_restr0.05571020
X-RAY DIFFRACTIONf_plane_restr0.00481159
X-RAY DIFFRACTIONf_dihedral_angle_d14.99952186
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS1.38291900801
ens_2d_2BBX-RAY DIFFRACTIONTorsion NCS1.06445407595
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.91-30.3433140.4702203X-RAY DIFFRACTION10.43
3-3.090.4014420.37576X-RAY DIFFRACTION29.39
3.09-3.20.4297890.35791080X-RAY DIFFRACTION56.83
3.2-3.330.33091310.34431551X-RAY DIFFRACTION79.79
3.33-3.480.37541600.33181866X-RAY DIFFRACTION97.4
3.48-3.670.33541710.3241926X-RAY DIFFRACTION99.62
3.67-3.90.31441610.2841889X-RAY DIFFRACTION99.56
3.9-4.20.32821740.23931911X-RAY DIFFRACTION99.43
4.2-4.620.25711450.21741930X-RAY DIFFRACTION99.76
4.62-5.290.28161780.20091937X-RAY DIFFRACTION99.72
5.29-6.650.27611820.26131885X-RAY DIFFRACTION99.76
6.66-43.270.25451730.20861911X-RAY DIFFRACTION99.67

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