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- PDB-6h50: Crystal structure of human KDM5B in complex with compound 34a -

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Basic information

Entry
Database: PDB / ID: 6h50
TitleCrystal structure of human KDM5B in complex with compound 34a
ComponentsLysine-specific demethylase 5B,Lysine-specific demethylase 5B
KeywordsOXIDOREDUCTASE / Histone demethylase / Inhibitor / transcription
Function / homology
Function and homology information


regulation of estradiol secretion / mammary duct terminal end bud growth / uterus morphogenesis / TFAP2 (AP-2) family regulates transcription of cell cycle factors / positive regulation of mammary gland epithelial cell proliferation / [histone H3]-trimethyl-L-lysine4 demethylase / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / lens fiber cell differentiation / histone H3K4 demethylase activity / cellular response to fibroblast growth factor stimulus ...regulation of estradiol secretion / mammary duct terminal end bud growth / uterus morphogenesis / TFAP2 (AP-2) family regulates transcription of cell cycle factors / positive regulation of mammary gland epithelial cell proliferation / [histone H3]-trimethyl-L-lysine4 demethylase / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / lens fiber cell differentiation / histone H3K4 demethylase activity / cellular response to fibroblast growth factor stimulus / branching involved in mammary gland duct morphogenesis / single fertilization / histone demethylase activity / response to fungicide / post-embryonic development / Chromatin modifications during the maternal to zygotic transition (MZT) / cellular response to leukemia inhibitory factor / HDMs demethylate histones / transcription corepressor activity / sequence-specific double-stranded DNA binding / rhythmic process / histone binding / nucleic acid binding / chromatin remodeling / negative regulation of DNA-templated transcription / chromatin / regulation of DNA-templated transcription / positive regulation of gene expression / DNA binding / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
: / : / : / : / Lysine-specific demethylase 5, C-terminal helical domain / Lysine-specific demethylase-like domain / PLU-1-like protein / Zinc finger, C5HC2-type / C5HC2 zinc finger / ARID/BRIGHT DNA binding domain ...: / : / : / : / Lysine-specific demethylase 5, C-terminal helical domain / Lysine-specific demethylase-like domain / PLU-1-like protein / Zinc finger, C5HC2-type / C5HC2 zinc finger / ARID/BRIGHT DNA binding domain / ARID DNA-binding domain / ARID DNA-binding domain superfamily / ARID/BRIGHT DNA binding domain / ARID domain profile. / BRIGHT, ARID (A/T-rich interaction domain) domain / JmjN domain / jmjN domain / JmjN domain profile. / Small domain found in the jumonji family of transcription factors / JmjC domain, hydroxylase / A domain family that is part of the cupin metalloenzyme superfamily. / JmjC domain / JmjC domain profile. / Zinc finger, PHD-type, conserved site / PHD-finger / Zinc finger PHD-type signature. / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-FO2 / : / PHOSPHATE ION / Lysine-specific demethylase 5B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.19 Å
AuthorsLe Bihan, Y.V. / Velupillai, S. / van Montfort, R.L.M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKC309/A11566 United Kingdom
CitationJournal: Eur.J.Med.Chem. / Year: 2019
Title: C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) ...Title: C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays.
Authors: Le Bihan, Y.V. / Lanigan, R.M. / Atrash, B. / McLaughlin, M.G. / Velupillai, S. / Malcolm, A.G. / England, K.S. / Ruda, G.F. / Mok, N.Y. / Tumber, A. / Tomlin, K. / Saville, H. / Shehu, E. / ...Authors: Le Bihan, Y.V. / Lanigan, R.M. / Atrash, B. / McLaughlin, M.G. / Velupillai, S. / Malcolm, A.G. / England, K.S. / Ruda, G.F. / Mok, N.Y. / Tumber, A. / Tomlin, K. / Saville, H. / Shehu, E. / McAndrew, C. / Carmichael, L. / Bennett, J.M. / Jeganathan, F. / Eve, P. / Donovan, A. / Hayes, A. / Wood, F. / Raynaud, F.I. / Fedorov, O. / Brennan, P.E. / Burke, R. / van Montfort, R.L.M. / Rossanese, O.W. / Blagg, J. / Bavetsias, V.
History
DepositionJul 23, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 12, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2024Group: 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: Lysine-specific demethylase 5B,Lysine-specific demethylase 5B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,68015
Polymers55,4581
Non-polymers1,22314
Water6,557364
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2150 Å2
ΔGint4 kcal/mol
Surface area20250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)142.360, 142.360, 152.780
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Lysine-specific demethylase 5B,Lysine-specific demethylase 5B / Cancer/testis antigen 31 / CT31 / Histone demethylase JARID1B / Jumonji/ARID domain-containing ...Cancer/testis antigen 31 / CT31 / Histone demethylase JARID1B / Jumonji/ARID domain-containing protein 1B / PLU-1 / Retinoblastoma-binding protein 2 homolog 1 / RBP2-H1


Mass: 55457.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM5B, JARID1B, PLU1, RBBP2H1 / Production host: Spodoptera frugiperda (fall armyworm) / Variant (production host): sf9
References: UniProt: Q9UGL1, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor

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Non-polymers , 7 types, 378 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#6: Chemical ChemComp-FO2 / 8-[4-(1-methylpiperidin-4-yl)pyrazol-1-yl]-3~{H}-pyrido[3,4-d]pyrimidin-4-one


Mass: 310.354 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H18N6O
#7: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 364 / Source method: isolated from a natural source / Formula: H2O

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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: 4.03 Å3/Da / Density % sol: 69.47 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 100 nL of protein is mixed with 200 nL of crystallisation solution containing 1.6 M Na/K phosphate, 0.1 M HEPES pH 7.5, and with 20 nL of seeds obtained in the same conditions. Inhibitor is ...Details: 100 nL of protein is mixed with 200 nL of crystallisation solution containing 1.6 M Na/K phosphate, 0.1 M HEPES pH 7.5, and with 20 nL of seeds obtained in the same conditions. Inhibitor is soaked in crystals by addition directly to the drops of DMSO dissolved compound

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 22, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.19→47.97 Å / Num. obs: 47457 / % possible obs: 99.9 % / Redundancy: 16.8 % / Biso Wilson estimate: 50.51 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.114 / Net I/σ(I): 18.3
Reflection shellResolution: 2.19→2.25 Å / Redundancy: 8.3 % / Rmerge(I) obs: 1.284 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 3450 / CC1/2: 0.494 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5a1f

5a1f


Resolution: 2.19→32.06 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.946 / SU R Cruickshank DPI: 0.146 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.157 / SU Rfree Blow DPI: 0.138 / SU Rfree Cruickshank DPI: 0.133
RfactorNum. reflection% reflectionSelection details
Rfree0.206 2333 4.92 %RANDOM
Rwork0.182 ---
obs0.183 47381 99.9 %-
Displacement parametersBiso mean: 54.77 Å2
Baniso -1Baniso -2Baniso -3
1--2.2699 Å20 Å20 Å2
2---2.2699 Å20 Å2
3---4.5398 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: 1 / Resolution: 2.19→32.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3588 0 63 365 4016
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013899HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.045325HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1279SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes81HARMONIC2
X-RAY DIFFRACTIONt_gen_planes597HARMONIC5
X-RAY DIFFRACTIONt_it3899HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.38
X-RAY DIFFRACTIONt_other_torsion17.37
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion487SEMIHARMONIC5
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_contact4622SEMIHARMONIC4
LS refinement shellResolution: 2.19→2.25 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2509 164 4.76 %
Rwork0.2429 3279 -
all0.2433 3443 -
obs--99.77 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.7031-0.05140.5781.011-0.1192.8631-0.0313-0.11230.04830.00460.01350.03690.2061-0.13760.0178-0.2095-0.07680.02110.0732-0.0527-0.142387.442667.373115.3516
21.58330.09940.34291.780.70872.4961-0.15240.11180.1843-0.05050.2180.1438-0.03060.2872-0.0656-0.1661-0.0049-0.01480.05330.0051-0.019755.354764.10245.4546
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|24 - 607}
2X-RAY DIFFRACTION2{A|608 - 754}

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