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- PDB-5k4l: Crystal structure of KDM5A in complex with a naphthyridone inhibitor -

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Basic information

Entry
Database: PDB / ID: 5k4l
TitleCrystal structure of KDM5A in complex with a naphthyridone inhibitor
Components
  • Lysine-specific demethylase 5A
  • Unknown Peptide
KeywordsOxidoreductase/Inhibitor / epigenetics / demethylase / jumonji / inhibitor / cancer / Oxidoreductase-Inhibitor complex
Function / homology
Function and homology information


facultative heterochromatin formation / [histone H3]-trimethyl-L-lysine4 demethylase / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / regulation of DNA-binding transcription factor activity / enzyme inhibitor activity / histone demethylase activity / methylated histone binding / Chromatin modifications during the maternal to zygotic transition (MZT) / circadian regulation of gene expression / HDMs demethylate histones ...facultative heterochromatin formation / [histone H3]-trimethyl-L-lysine4 demethylase / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / regulation of DNA-binding transcription factor activity / enzyme inhibitor activity / histone demethylase activity / methylated histone binding / Chromatin modifications during the maternal to zygotic transition (MZT) / circadian regulation of gene expression / HDMs demethylate histones / chromatin DNA binding / histone binding / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / regulation of DNA-templated transcription / chromatin / nucleolus / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
ARID DNA-binding domain / : / : / : / : / : / Lysine-specific demethylase 5, C-terminal helical domain / Lysine-specific demethylase-like domain / PLU-1-like protein / Zinc finger, C5HC2-type ...ARID 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 / Cupin / 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 / DNA polymerase; domain 1 / Zinc finger, RING/FYVE/PHD-type / Jelly Rolls / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-6QN / NICKEL (II) ION / Lysine-specific demethylase 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 3.179 Å
AuthorsKiefer, J.R. / Vinogradova, M.V.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors.
Authors: Labadie, S.S. / Dragovich, P.S. / Cummings, R.T. / Deshmukh, G. / Gustafson, A. / Han, N. / Harmange, J.C. / Kiefer, J.R. / Li, Y. / Liang, J. / Liederer, B.M. / Liu, Y. / Manieri, W. / Mao, ...Authors: Labadie, S.S. / Dragovich, P.S. / Cummings, R.T. / Deshmukh, G. / Gustafson, A. / Han, N. / Harmange, J.C. / Kiefer, J.R. / Li, Y. / Liang, J. / Liederer, B.M. / Liu, Y. / Manieri, W. / Mao, W. / Murray, L. / Ortwine, D.F. / Trojer, P. / VanderPorten, E. / Vinogradova, M. / Wen, L.
History
DepositionMay 20, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 10, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 24, 2016Group: Database references
Revision 1.2Sep 7, 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 5A
B: Lysine-specific demethylase 5A
F: Unknown Peptide
G: Unknown Peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)183,99112
Polymers183,1464
Non-polymers8458
Water36020
1
A: Lysine-specific demethylase 5A
B: Lysine-specific demethylase 5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)182,25310
Polymers181,4082
Non-polymers8458
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)159.141, 159.141, 92.109
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31
DetailsThe biological assembly is dimer. Chains F,G are parts of molecule 1

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABFG

#1: Protein Lysine-specific demethylase 5A / Histone demethylase JARID1A / Jumonji/ARID domain-containing protein 1A / Retinoblastoma-binding ...Histone demethylase JARID1A / Jumonji/ARID domain-containing protein 1A / Retinoblastoma-binding protein 2 / RBBP-2


Mass: 90703.938 Da / Num. of mol.: 2 / Fragment: UNP residues 12-797
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM5A, JARID1A, RBBP2, RBP2 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: P29375, 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
#2: Protein/peptide Unknown Peptide


Mass: 869.063 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: A LARGE SECTION OF MOLECULE 1 IS MISSING IN THE COORDINATES AND MOLECULE 2 IS PROBABLY A PART OF MOLECULE 1
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM5A, JARID1A, RBBP2, RBP2 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9

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Non-polymers , 4 types, 28 molecules

#3: Chemical ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ni
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-6QN / ~{N}-ethyl-4-oxidanyl-2-oxidanylidene-1~{H}-1,7-naphthyridine-3-carboxamide


Mass: 233.223 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H11N3O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 3.71 Å3/Da / Density % sol: 66.87 %
Crystal growTemperature: 292 K / Method: vapor diffusion / pH: 7.3 / Details: 20% PEG3350, 0.1 M HEPES, pH 7.3, and 12% glycerol

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 19, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
Reflection twinOperator: k,h,-l / Fraction: 0.5
ReflectionResolution: 3.179→35 Å / Num. obs: 40754 / % possible obs: 93.3 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.099 / Net I/σ(I): 7.8
Reflection shellResolution: 3.179→3.26 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.502 / Mean I/σ(I) obs: 1.1 / % possible all: 90.1

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHENIX1.8.2_1309refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementResolution: 3.179→34.503 Å / Cross valid method: FREE R-VALUE / σ(F): 1.99 / Phase error: 26.35
RfactorNum. reflection% reflection
Rfree0.257 2181 5.35 %
Rwork0.2217 --
obs0.2237 40747 92.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 256.66 Å2 / Biso mean: 105.01 Å2 / Biso min: 22.24 Å2
Refinement stepCycle: final / Resolution: 3.179→34.503 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9188 0 162 20 9370
Biso mean--102.9 37.91 -
Num. residues----1154
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0119602
X-RAY DIFFRACTIONf_angle_d0.96513055
X-RAY DIFFRACTIONf_chiral_restr0.0551402
X-RAY DIFFRACTIONf_plane_restr0.0051713
X-RAY DIFFRACTIONf_dihedral_angle_d15.8353499
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.1794-3.25330.33371270.29882315244280
3.2533-3.33460.34421290.27172512264186
3.3346-3.42460.31881400.26722561270187
3.4246-3.52520.31271180.24532538265688
3.5252-3.63880.30261570.24882617277490
3.6388-3.76860.31181360.28412723285993
3.7686-3.91920.27991220.23352457257984
3.9192-4.09720.24971040.21372238234276
4.0972-4.31260.2721480.21022422257083
4.3126-4.58190.25481450.19922708285392
4.5819-4.93430.24941400.19932686282692
4.9343-5.42820.22371410.20032751289293
5.4282-6.20770.25251440.22522706285094
6.2077-7.79840.24531450.21082703284892
7.7984-30.07620.20031660.18862734290093
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)
10.64280.0763-0.52520.4668-0.66641.2251-0.0133-0.1643-0.01130.22890.0265-0.0356-0.22210.3105-0.03480.82230.1540.17950.519-0.01530.2519188.139514.5627-4.9661
20.70640.75340.29660.82370.24460.39720.14040.0717-0.0416-0.04020.1903-0.28010.0695-0.0957-0.19460.40720.0709-0.10040.8212-0.02151.4937182.2669-17.2061-30.6563
31.0990.18410.20350.96830.35920.8110.26820.2879-0.00510.04630.148-0.097-0.19-0.1289-0.2960.54790.07650.22260.7703-0.22811.1707193.16312.8297-17.6765
40.22030.19820.32440.70260.60420.66380.18170.32-0.18730.00940.0265-0.12520.0578-0.0447-0.23860.53810.06870.25940.773-0.00031.2813172.8947-2.0328-16.7871
51.33910.1873-0.30621.1934-0.34351.0472-0.0632-0.2372-0.34710.16610.16190.14860.28180.05-0.1080.68110.10160.10030.5037-0.07920.7151183.1115-14.14110.8828
60.58590.6124-0.1061.2876-0.05290.0521-0.0104-0.0060.02940.01880.1118-0.1363-0.03260.0387-0.1021.53170.20190.01051.43560.27281.3431191.88462.743122.4344
71.0289-0.49750.11870.56290.10440.5449-0.08770.0550.111-0.1147-0.1207-0.09780.15290.17640.11110.71520.04620.20580.84150.16410.9327236.9094-13.7211-19.1397
80.21610.06810.13840.17720.04960.20260.0075-0.05690.0770.051-0.1151-0.0109-0.0845-0.0486-0.09080.84950.1373-0.03980.78650.07760.1128212.2305-34.54566.5173
90.30770.2193-0.34711.5777-0.68610.5260.0126-0.0913-0.07860.1153-0.09380.07170.02520.06530.02760.77080.1647-0.24110.8354-0.16840.4098220.6549-21.3648.8079
100.5195-0.08050.2370.6932-0.15190.5278-0.0403-0.03610.05450.0770.0417-0.0334-0.03750.05110.22650.6613-0.0228-0.30850.8174-0.01840.3363225.5038-11.5575-9.3853
110.2038-0.03960.01470.6701-0.03790.37860.0084-0.036-0.0646-0.0492-0.03120.0720.0671-0.1019-0.21950.58650.1167-0.19610.74080.07950.2003228.6233-27.7492-8.9927
120.7440.21550.54130.44070.25711.9290.05130.2969-0.3753-0.25820.05320.31480.2642-0.0454-0.14530.56180.0933-0.30220.6597-0.20440.4873220.475-27.7607-25.054
132.14710.60640.51853.366-1.27751.24230.04420.0817-0.3937-0.2450.02790.51430.2882-0.2035-0.05540.6244-0.1027-0.26470.8096-0.02261.2133201.3224-37.8825-25.7727
141.36080.5973-0.720.2971-0.43960.95480.06790.3666-0.0744-0.22280.0494-0.0058-0.00140.1563-0.0781.08-0.1519-0.22011.21410.00151.2838216.4186-26.19-40.6031
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 12 through 62 )A12 - 62
2X-RAY DIFFRACTION2chain 'A' and (resid 63 through 173 )A63 - 173
3X-RAY DIFFRACTION3chain 'A' and (resid 174 through 498 )A174 - 498
4X-RAY DIFFRACTION4chain 'A' and (resid 499 through 547 )A499 - 547
5X-RAY DIFFRACTION5chain 'A' and (resid 548 through 723 )A548 - 723
6X-RAY DIFFRACTION6chain 'A' and (resid 724 through 785 )A724 - 785
7X-RAY DIFFRACTION7chain 'B' and (resid 12 through 62 )B12 - 62
8X-RAY DIFFRACTION8chain 'B' and (resid 63 through 173 )B63 - 173
9X-RAY DIFFRACTION9chain 'B' and (resid 174 through 378 )B174 - 378
10X-RAY DIFFRACTION10chain 'B' and (resid 379 through 462 )B379 - 462
11X-RAY DIFFRACTION11chain 'B' and (resid 463 through 557 )B463 - 557
12X-RAY DIFFRACTION12chain 'B' and (resid 558 through 655 )B558 - 655
13X-RAY DIFFRACTION13chain 'B' and (resid 656 through 699 )B656 - 699
14X-RAY DIFFRACTION14chain 'B' and (resid 700 through 785 )B700 - 785

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