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- PDB-7m40: Discovery of small molecule antagonists of human Retinoblastoma B... -

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Basic information

Entry
Database: PDB / ID: 7m40
TitleDiscovery of small molecule antagonists of human Retinoblastoma Binding Protein 4 (RBBP4)
ComponentsHistone-binding protein RBBP4
KeywordsGENE REGULATION / RBBP4 / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


CAF-1 complex / NURF complex / NuRD complex / regulation of cell fate specification / negative regulation of stem cell population maintenance / DNA replication-dependent chromatin assembly / ESC/E(Z) complex / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / regulation of stem cell differentiation / Transcription of E2F targets under negative control by DREAM complex ...CAF-1 complex / NURF complex / NuRD complex / regulation of cell fate specification / negative regulation of stem cell population maintenance / DNA replication-dependent chromatin assembly / ESC/E(Z) complex / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / regulation of stem cell differentiation / Transcription of E2F targets under negative control by DREAM complex / Polo-like kinase mediated events / G1/S-Specific Transcription / positive regulation of stem cell population maintenance / ATPase complex / Sin3-type complex / Transcriptional Regulation by E2F6 / RNA Polymerase I Transcription Initiation / histone deacetylase complex / G0 and Early G1 / Cyclin E associated events during G1/S transition / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / Cyclin A:Cdk2-associated events at S phase entry / Deposition of new CENPA-containing nucleosomes at the centromere / Regulation of TP53 Activity through Acetylation / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / negative regulation of cell migration / PRC2 methylates histones and DNA / Regulation of endogenous retroelements by KRAB-ZFP proteins / Regulation of PTEN gene transcription / Defective pyroptosis / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / HDACs deacetylate histones / negative regulation of transforming growth factor beta receptor signaling pathway / brain development / PKMTs methylate histone lysines / histone deacetylase binding / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / nucleosome assembly / histone binding / Oxidative Stress Induced Senescence / Potential therapeutics for SARS / DNA replication / chromosome, telomeric region / chromatin remodeling / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of cell population proliferation / negative regulation of DNA-templated transcription / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / nucleus / cytosol
Similarity search - Function
Histone-binding protein RBBP4, N-terminal / Histone-binding protein RBBP4 or subunit C of CAF1 complex / : / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats ...Histone-binding protein RBBP4, N-terminal / Histone-binding protein RBBP4 or subunit C of CAF1 complex / : / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Chem-YQJ / Histone-binding protein RBBP4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.88 Å
AuthorsPerveen, S. / Dong, A. / Tempel, W. / Zepeda-Velazquez, C. / Abbey, M. / McLeod, D. / Marcellus, R. / Mohammed, M. / Ensan, D. / Panagopoulos, D. ...Perveen, S. / Dong, A. / Tempel, W. / Zepeda-Velazquez, C. / Abbey, M. / McLeod, D. / Marcellus, R. / Mohammed, M. / Ensan, D. / Panagopoulos, D. / Trush, V. / Gibson, E. / Brown, P.J. / Arrowsmith, C.H. / Schapira, M. / Al-awar, R. / Vedadi, M. / Structural Genomics Consortium (SGC)
CitationJournal: To Be Published
Title: Discovery of small molecule antagonists of human Retinoblastoma Binding Protein 4 (RBBP4)
Authors: Perveen, S. / Zepeda-Velazquez, C. / Abbey, M. / McLeod, D. / Marcellus, R. / Mohammed, M. / Ensan, D. / Panagopoulos, D. / Trush, V. / Gibson, E. / Tempel, W. / Brown, P.J. / Arrowsmith, C. ...Authors: Perveen, S. / Zepeda-Velazquez, C. / Abbey, M. / McLeod, D. / Marcellus, R. / Mohammed, M. / Ensan, D. / Panagopoulos, D. / Trush, V. / Gibson, E. / Tempel, W. / Brown, P.J. / Arrowsmith, C.H. / Schapira, M. / Al-awar, R. / Vedadi, M. / Structural Genomics Consortium (SGC)
History
DepositionMar 19, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 12, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone-binding protein RBBP4
B: Histone-binding protein RBBP4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,6254
Polymers99,8202
Non-polymers8052
Water6,017334
1
A: Histone-binding protein RBBP4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,3122
Polymers49,9101
Non-polymers4031
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone-binding protein RBBP4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,3122
Polymers49,9101
Non-polymers4031
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.820, 59.857, 102.011
Angle α, β, γ (deg.)90.000, 93.730, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Histone-binding protein RBBP4 / Chromatin assembly factor 1 subunit C / CAF-1 subunit C / Chromatin assembly factor I p48 subunit / ...Chromatin assembly factor 1 subunit C / CAF-1 subunit C / Chromatin assembly factor I p48 subunit / CAF-I 48 kDa subunit / CAF-I p48 / Nucleosome-remodeling factor subunit RBAP48 / Retinoblastoma-binding protein 4 / RBBP-4 / Retinoblastoma-binding protein p48


Mass: 49909.887 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBBP4, RBAP48 / Cell (production host): SF9 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q09028
#2: Chemical ChemComp-YQJ / N~3~-{4-[3-(dimethylamino)pyrrolidin-1-yl]-6,7-dimethoxyquinazolin-2-yl}-N~1~,N~1~-dimethylpropane-1,3-diamine


Mass: 402.534 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H34N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 334 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.31 Å3/Da / Density % sol: 46.85 % / Description: Hexagon shape
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 23% PEG3350, 0.2N ammonium acetate, 0.1M Bis-tris pH5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS3 X 6M / Detector: PIXEL / Date: Oct 19, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.88→50 Å / Num. obs: 73841 / % possible obs: 98 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.03 / Rrim(I) all: 0.071 / Χ2: 0.611 / Net I/σ(I): 5.5 / Num. measured all: 401380
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.88-1.914.90.73534840.8690.3430.8150.43893.8
1.91-1.9550.63436040.890.2950.7030.46295.5
1.95-1.985.10.57136280.9070.2650.6320.46297.5
1.98-2.035.20.46937040.9410.2190.520.4698.6
2.03-2.075.30.41136880.9570.1910.4550.47898.6
2.07-2.125.30.34436790.970.1590.3810.47698.2
2.12-2.175.20.28535910.9740.1350.3160.48696.5
2.17-2.235.30.24135980.9820.1120.2670.49395.1
2.23-2.295.70.23337180.9740.1040.2560.51399.7
2.29-2.375.70.20237520.9840.0910.2230.51599.7
2.37-2.455.70.17337000.9890.0770.190.5299.4
2.45-2.555.70.14937440.990.0670.1640.52699.5
2.55-2.675.60.11437030.9930.0510.1250.55999.1
2.67-2.815.20.09236840.9950.0430.1020.61597.2
2.81-2.985.70.07636910.9960.0340.0830.65498.1
2.98-3.215.90.06437600.9970.0280.070.77799.3
3.21-3.545.80.05137630.9980.0230.0560.94299.4
3.54-4.055.40.04637250.9980.0210.0511.00698.3
4.05-5.15.60.03937810.9980.0170.0430.91198.6
5.1-505.50.03738440.9980.0170.0410.76898.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PHASERphasing
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6BW3

6bw3


Resolution: 1.88→46.99 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.954 / SU B: 4.402 / SU ML: 0.121 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.129 / ESU R Free: 0.133 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2357 699 1 %RANDOM
Rwork0.1836 ---
obs0.184 72452 98.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 115.05 Å2 / Biso mean: 38.944 Å2 / Biso min: 21.96 Å2
Baniso -1Baniso -2Baniso -3
1-4.2 Å2-0 Å2-0.25 Å2
2---3.37 Å2-0 Å2
3----0.8 Å2
Refinement stepCycle: final / Resolution: 1.88→46.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6041 0 45 337 6423
Biso mean--69.86 43.3 -
Num. residues----780
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0136283
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175408
X-RAY DIFFRACTIONr_angle_refined_deg1.381.6278599
X-RAY DIFFRACTIONr_angle_other_deg1.2761.57812557
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.935780
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.23623.909307
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.30815925
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3521520
X-RAY DIFFRACTIONr_chiral_restr0.0650.2833
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.027236
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021272
LS refinement shellResolution: 1.88→1.929 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.271 51 -
Rwork0.295 5179 -
all-5230 -
obs--94.8 %

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