[English] 日本語
Yorodumi
- PDB-8rq9: Crystal structure of PROTAC CFT-1297 in complex with CRBN-midi an... -

+
Open data


ID or keywords:

Loading...

-
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 / locomotory exploration behavior / RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / positive regulation of Wnt signaling pathway / negative regulation by host of viral transcription / negative regulation of protein-containing complex assembly / positive regulation of T-helper 17 cell lineage commitment ...negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / positive regulation of Wnt signaling pathway / negative regulation by host of viral transcription / negative regulation of protein-containing complex assembly / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / lysine-acetylated histone binding / positive regulation of protein-containing complex assembly / p53 binding / chromosome / regulation of inflammatory response / proteasome-mediated ubiquitin-dependent protein catabolic process / positive regulation of canonical NF-kappaB signal transduction / transmembrane transporter binding / Potential therapeutics for SARS / transcription coactivator activity / transcription cis-regulatory region binding / protein ubiquitination / chromatin remodeling / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / perinuclear region of cytoplasm / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / membrane / nucleus / metal ion binding / cytosol / cytoplasm
Similarity search - Function
Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon protease, N-terminal domain superfamily / Lon N-terminal domain profile. / Lon protease, N-terminal domain / 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 protease, N-terminal domain superfamily / Lon N-terminal domain profile. / Lon protease, N-terminal domain / 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 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / : / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / 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: To Be Published
Title: Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders
Authors: Kroupova, A. / Zollman, D. / Ciulli, A.
History
DepositionJan 17, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 25, 2024Provider: repository / Type: Initial release

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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


  • defined by author
  • Evidence: gel filtration
  • 53.4 kDa, 2 polymers
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


  • defined by author
  • Evidence: gel filtration
  • 53.4 kDa, 2 polymers
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_1CFTCFTCFTCFTAE501
d_21ens_1ASNASNTHRTHRCD48 - 4259 - 328
d_22ens_1CFTCFTCFTCFTCG501
d_11ens_2ASPASPALAALABB337 - 3667 - 36
d_12ens_2ALAALAPROPROBB371 - 45841 - 128
d_21ens_2ASPASPPROPRODC337 - 4587 - 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

-
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.
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

-
Experimental details

-
Experiment

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

-
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

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbjlvh1.pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more