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- PDB-7q6u: Crystal structure of the bromodomain of ATAD2 with phenol HTS hit... -

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Basic information

Entry
Database: PDB / ID: 7q6u
TitleCrystal structure of the bromodomain of ATAD2 with phenol HTS hit (cpd 6)
ComponentsATPase family AAA domain-containing protein 2
KeywordsGENE REGULATION / bromodomain / epigenetics
Function / homology
Function and homology information


Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / histone binding / chromatin binding / positive regulation of DNA-templated transcription / ATP hydrolysis activity / positive regulation of transcription by RNA polymerase II / extracellular exosome / nucleoplasm / ATP binding / nucleus
Similarity search - Function
ATPase family AAA domain-containing protein ATAD2-like / AAA ATPase, AAA+ lid domain / AAA+ lid domain / ATPase, AAA-type, conserved site / AAA-protein family signature. / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / Bromodomain / Bromodomain profile. / bromo domain ...ATPase family AAA domain-containing protein ATAD2-like / AAA ATPase, AAA+ lid domain / AAA+ lid domain / ATPase, AAA-type, conserved site / AAA-protein family signature. / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-963 / ATPase family AAA domain-containing protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsPatel, S.J. / Winter-Holt, J.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models.
Authors: Winter-Holt, J.J. / Bardelle, C. / Chiarparin, E. / Dale, I.L. / Davey, P.R.J. / Davies, N.L. / Denz, C. / Fillery, S.M. / Guerot, C.M. / Han, F. / Hughes, S.J. / Kulkarni, M. / Liu, Z. / ...Authors: Winter-Holt, J.J. / Bardelle, C. / Chiarparin, E. / Dale, I.L. / Davey, P.R.J. / Davies, N.L. / Denz, C. / Fillery, S.M. / Guerot, C.M. / Han, F. / Hughes, S.J. / Kulkarni, M. / Liu, Z. / Milbradt, A. / Moss, T.A. / Niu, H. / Patel, J. / Rabow, A.A. / Schimpl, M. / Shi, J. / Sun, D. / Yang, D. / Guichard, S.
History
DepositionNov 9, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 19, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 9, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATPase family AAA domain-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,1105
Polymers15,4541
Non-polymers6574
Water3,459192
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area480 Å2
ΔGint-33 kcal/mol
Surface area7990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.039, 79.039, 137.850
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-1203-

SO4

21A-1406-

HOH

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Components

#1: Protein ATPase family AAA domain-containing protein 2 / AAA nuclear coregulator cancer-associated protein / ANCCA


Mass: 15453.514 Da / Num. of mol.: 1 / Fragment: bromodomain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ATAD2, L16, PRO2000 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): Gold / References: UniProt: Q6PL18, EC: 3.6.1.3
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-963 / (1R,9S)-13-(3,5-dimethoxy-4-oxidanyl-phenyl)carbonyl-11,13-diazatricyclo[7.3.1.0^{2,7}]trideca-2,4,6-trien-10-one


Mass: 368.383 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20N2O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 192 / 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: 4.02 Å3/Da / Density % sol: 69.42 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.25
Details: ATAD2 (981-1108) at 12 mg/ml in 25 mM Tris pH 9.7, 300 mM NaCl, 0.5 mM TCEP crystallised from 20% PEG 3350, 0.2 M ammonium sulfate, 0.1 M Bis-Tris pH 6.25. Ligands were introduced by ...Details: ATAD2 (981-1108) at 12 mg/ml in 25 mM Tris pH 9.7, 300 mM NaCl, 0.5 mM TCEP crystallised from 20% PEG 3350, 0.2 M ammonium sulfate, 0.1 M Bis-Tris pH 6.25. Ligands were introduced by soaking, cryo-protection with 20 % glycerol.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ / Wavelength: 1.5406 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Jul 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5406 Å / Relative weight: 1
ReflectionResolution: 1.95→68.93 Å / Num. obs: 19205 / % possible obs: 99.8 % / Redundancy: 5.8 % / Biso Wilson estimate: 26.76 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.042 / Rrim(I) all: 0.104 / Net I/σ(I): 17 / Num. measured all: 112343
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.95-2.115.30.6672029238320.7470.3080.7382.999.1
5.17-68.935.40.0266417119810.0120.02950.599.5

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Processing

Software
NameVersionClassification
Aimless0.2.17data scaling
BUSTER2.11.5refinement
PDB_EXTRACT3.27data extraction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 1.95→48.57 Å / Cor.coef. Fo:Fc: 0.9431 / Cor.coef. Fo:Fc free: 0.9424 / SU R Cruickshank DPI: 0.112 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.127 / SU Rfree Blow DPI: 0.111 / SU Rfree Cruickshank DPI: 0.102
RfactorNum. reflection% reflectionSelection details
Rfree0.1993 973 5.08 %RANDOM
Rwork0.1858 ---
obs0.1865 19140 99.32 %-
Displacement parametersBiso max: 99.7 Å2 / Biso mean: 31.25 Å2 / Biso min: 11.51 Å2
Baniso -1Baniso -2Baniso -3
1-0.1181 Å20 Å20 Å2
2--0.1181 Å20 Å2
3----0.2361 Å2
Refine analyzeLuzzati coordinate error obs: 0.204 Å
Refinement stepCycle: final / Resolution: 1.95→48.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1084 0 42 192 1318
Biso mean--45.37 44.36 -
Num. residues----130
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d439SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes36HARMONIC2
X-RAY DIFFRACTIONt_gen_planes167HARMONIC5
X-RAY DIFFRACTIONt_it1163HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion153SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1528SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1163HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg1584HARMONIC20.88
X-RAY DIFFRACTIONt_omega_torsion2.61
X-RAY DIFFRACTIONt_other_torsion16.62
LS refinement shellResolution: 1.95→2.06 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2259 136 5.18 %
Rwork0.2279 2490 -
all0.2278 2626 -
obs--99.32 %

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