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- PDB-5anq: inhibitors of JumonjiC domain-containing histone demethylases -

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Basic information

Entry
Database: PDB / ID: 5anq
Titleinhibitors of JumonjiC domain-containing histone demethylases
ComponentsLYSINE-SPECIFIC DEMETHYLASE 4A
KeywordsOXIDOREDUCTASE / EPIGENETICS / HISTONE DEMETHYLASES / INHIBITORS / JUMONJIC DOMAIN / VIRTUAL SCREENING
Function / homology
Function and homology information


[histone H3]-trimethyl-L-lysine36 demethylase / histone demethylation / histone H3-K36 demethylation / histone H3-methyl-lysine-36 demethylase activity / cardiac muscle hypertrophy in response to stress / [histone H3]-trimethyl-L-lysine9 demethylase / negative regulation of histone H3-K9 trimethylation / histone H3-K9 demethylation / histone H3-methyl-lysine-9 demethylase activity / negative regulation of astrocyte differentiation ...[histone H3]-trimethyl-L-lysine36 demethylase / histone demethylation / histone H3-K36 demethylation / histone H3-methyl-lysine-36 demethylase activity / cardiac muscle hypertrophy in response to stress / [histone H3]-trimethyl-L-lysine9 demethylase / negative regulation of histone H3-K9 trimethylation / histone H3-K9 demethylation / histone H3-methyl-lysine-9 demethylase activity / negative regulation of astrocyte differentiation / pericentric heterochromatin / histone demethylase activity / negative regulation of cell death / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / negative regulation of autophagy / methylated histone binding / response to nutrient levels / positive regulation of neuron differentiation / HDMs demethylate histones / fibrillar center / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromatin remodeling / negative regulation of gene expression / negative regulation of transcription, DNA-templated / ubiquitin protein ligase binding / positive regulation of gene expression / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Lysine-specific demethylase 4, Tudor domain / Jumonji domain-containing protein 2A Tudor domain / Tudor domain / Tudor domain / Small domain found in the jumonji family of transcription factors / JmjN domain profile. / JmjN domain / jmjN domain / Extended PHD (ePHD) domain / Extended PHD (ePHD) domain profile. ...Lysine-specific demethylase 4, Tudor domain / Jumonji domain-containing protein 2A Tudor domain / Tudor domain / Tudor domain / Small domain found in the jumonji family of transcription factors / JmjN domain profile. / JmjN domain / jmjN domain / Extended PHD (ePHD) domain / Extended PHD (ePHD) domain profile. / Cupin / JmjC domain, hydroxylase / A domain family that is part of the cupin metalloenzyme superfamily. / JmjC domain profile. / JmjC domain / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Zinc finger, RING/FYVE/PHD-type / Jelly Rolls / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-5YQ / : / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsRoatsch, M. / Robaa, D. / Pippel, M. / Nettleship, J.E. / Reddivari, Y. / Bird, L.E. / Hoffmann, I. / Franz, H. / Owens, R.J. / Schuele, R. ...Roatsch, M. / Robaa, D. / Pippel, M. / Nettleship, J.E. / Reddivari, Y. / Bird, L.E. / Hoffmann, I. / Franz, H. / Owens, R.J. / Schuele, R. / Flaig, R. / Sippl, W. / Jung, M.
CitationJournal: Fut.Med.Chem. / Year: 2016
Title: Substituted 2-(2-Aminopyrimidin-4-Yl)Pyridine-4-Carboxylates as Potent Inhibitors of Jumonjic Domain-Containing Histone Demethylases.
Authors: Roatsch, M. / Robaa, D. / Pippel, M. / Nettleship, J.E. / Reddivari, Y. / Bird, L.E. / Hoffmann, I. / Franz, H. / Owens, R.J. / Schole, R. / Flaig, R. / Sippl, W. / Jung, M.
History
DepositionSep 7, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 23, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 28, 2016Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: LYSINE-SPECIFIC DEMETHYLASE 4A
B: LYSINE-SPECIFIC DEMETHYLASE 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,91816
Polymers83,5352
Non-polymers1,38314
Water6,323351
1
B: LYSINE-SPECIFIC DEMETHYLASE 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4959
Polymers41,7681
Non-polymers7278
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
A: LYSINE-SPECIFIC DEMETHYLASE 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4247
Polymers41,7681
Non-polymers6566
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)100.694, 149.271, 57.527
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein LYSINE-SPECIFIC DEMETHYLASE 4A / JMJC DOMAIN-CONTAINING HISTONE DEMETHYLATION PROTEIN 3A / JUMONJI DOMAIN-CONTAINING PROTEIN 2A


Mass: 41767.543 Da / Num. of mol.: 2 / Fragment: JMJN, JMJC, RESIDUES 1-359
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): ROSETTA PLYSS
References: UniProt: O75164, [histone H3]-dimethyl-L-lysine36 demethylase

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Non-polymers , 6 types, 365 molecules

#2: Chemical ChemComp-5YQ / 2-{2-[(pyridin-3-ylmethyl)amino]pyrimidin-4-yl}pyridine-4-carboxylic acid


Mass: 307.307 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H13N5O2
#3: Chemical ChemComp-FE2 / FE (II) ION


Mass: 55.845 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 351 / 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: 2.59 Å3/Da / Density % sol: 52 % / Description: NONE
Crystal growDetails: 0.233 M LITHIUM SULFATE, 24% PEG 3350, 0.1 M HEPES PH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 17, 2014 / Details: MIRRORS
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2→49.76 Å / Num. obs: 59001 / % possible obs: 99 % / Observed criterion σ(I): 1.2 / Redundancy: 4.5 % / Biso Wilson estimate: 43.7 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 18.3
Reflection shellResolution: 2→2.05 Å / Redundancy: 4.5 % / Rmerge(I) obs: 1.15 / Mean I/σ(I) obs: 1.2 / % possible all: 94.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0123refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2OX0

2ox0


Resolution: 2→49.76 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.949 / Cross valid method: THROUGHOUT / ESU R: 0.17 / ESU R Free: 0.157 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.23242 2918 4.9 %RANDOM
Rwork0.18939 ---
obs0.19151 56037 98.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 46.636 Å2
Baniso -1Baniso -2Baniso -3
1--0.69 Å20 Å20 Å2
2--0.03 Å20 Å2
3---0.66 Å2
Refinement stepCycle: LAST / Resolution: 2→49.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5700 0 74 351 6125
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0195959
X-RAY DIFFRACTIONr_bond_other_d00.025474
X-RAY DIFFRACTIONr_angle_refined_deg1.4711.9418045
X-RAY DIFFRACTIONr_angle_other_deg3.8352.99212617
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3065692
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.25623.252286
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.2215997
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2371538
X-RAY DIFFRACTIONr_chiral_restr0.0870.2816
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0216642
X-RAY DIFFRACTIONr_gen_planes_other0.0350.021460
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9324.3362774
X-RAY DIFFRACTIONr_mcbond_other2.934.3352773
X-RAY DIFFRACTIONr_mcangle_it4.3386.4913464
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.7094.8153184
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.997→2.049 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.337 214 -
Rwork0.326 3883 -
obs--94.44 %

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