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- PDB-5f2w: Crystal structure of human KDM4A in complex with compound 16 -

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Open data


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Basic information

Entry
Database: PDB / ID: 5f2w
TitleCrystal structure of human KDM4A in complex with compound 16
ComponentsLysine-specific demethylase 4A
KeywordsOxidoreductase/Inhibitor / Epigenetics / Demethylase / Inhibitor / Oxidoreductase-Inhibitor Complex
Function / homology
Function and homology information


[histone H3]-trimethyl-L-lysine36 demethylase / histone H3K36me2/H3K36me3 demethylase activity / apoptotic chromosome condensation / histone H3K36 demethylase activity / cardiac muscle hypertrophy in response to stress / histone H3K9me2/H3K9me3 demethylase activity / [histone H3]-trimethyl-L-lysine9 demethylase / histone H3K9 demethylase activity / negative regulation of astrocyte differentiation / histone demethylase activity ...[histone H3]-trimethyl-L-lysine36 demethylase / histone H3K36me2/H3K36me3 demethylase activity / apoptotic chromosome condensation / histone H3K36 demethylase activity / cardiac muscle hypertrophy in response to stress / histone H3K9me2/H3K9me3 demethylase activity / [histone H3]-trimethyl-L-lysine9 demethylase / histone H3K9 demethylase activity / negative regulation of astrocyte differentiation / histone demethylase activity / pericentric heterochromatin / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / methylated histone binding / positive regulation of neuron differentiation / negative regulation of autophagy / response to nutrient levels / HDMs demethylate histones / fibrillar center / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / regulation of gene expression / chromatin remodeling / negative regulation of gene expression / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / chromatin / 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 / PHD-finger / PHD-zinc-finger like domain / JmjN domain ...: / : / : / Lysine-specific demethylase 4, Tudor domain / Jumonji domain-containing protein 2A Tudor domain / Tudor domain / Tudor domain / PHD-finger / PHD-zinc-finger like domain / JmjN domain / jmjN domain / JmjN domain profile. / Small domain found in the jumonji family of transcription factors / 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 / JmjC domain profile. / 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-5UP / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsLe Bihan, Y.-V. / Dempster, S. / Westwood, I.M. / van Montfort, R.L.M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKC309/A11566 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2016
Title: 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.
Authors: Bavetsias, V. / Lanigan, R.M. / Ruda, G.F. / Atrash, B. / McLaughlin, M.G. / Tumber, A. / Mok, N.Y. / Le Bihan, Y.V. / Dempster, S. / Boxall, K.J. / Jeganathan, F. / Hatch, S.B. / Savitsky, ...Authors: Bavetsias, V. / Lanigan, R.M. / Ruda, G.F. / Atrash, B. / McLaughlin, M.G. / Tumber, A. / Mok, N.Y. / Le Bihan, Y.V. / Dempster, S. / Boxall, K.J. / Jeganathan, F. / Hatch, S.B. / Savitsky, P. / Velupillai, S. / Krojer, T. / England, K.S. / Sejberg, J. / Thai, C. / Donovan, A. / Pal, A. / Scozzafava, G. / Bennett, J.M. / Kawamura, A. / Johansson, C. / Szykowska, A. / Gileadi, C. / Burgess-Brown, N.A. / von Delft, F. / Oppermann, U. / Walters, Z. / Shipley, J. / Raynaud, F.I. / Westaway, S.M. / Prinjha, R.K. / Fedorov, O. / Burke, R. / Schofield, C.J. / Westwood, I.M. / Bountra, C. / Muller, S. / van Montfort, R.L. / Brennan, P.E. / Blagg, J.
History
DepositionDec 2, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jan 20, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 9, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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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
C: Lysine-specific demethylase 4A
D: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,70146
Polymers167,4184
Non-polymers3,28242
Water3,873215
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A: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4708
Polymers41,8551
Non-polymers6157
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,82614
Polymers41,8551
Non-polymers97213
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,70212
Polymers41,8551
Non-polymers84811
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,70212
Polymers41,8551
Non-polymers84811
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.390, 102.040, 142.150
Angle α, β, γ (deg.)90.00, 99.70, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Lysine-specific demethylase 4A / JmjC domain-containing histone demethylation protein 3A / Jumonji domain-containing protein 2A / ...JmjC domain-containing histone demethylation protein 3A / Jumonji domain-containing protein 2A / Histone Lysine Demethylase 4A (KDM4A)


Mass: 41854.617 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM4A, JHDM3A, JMJD2, JMJD2A, KIAA0677 / Plasmid: pNIC28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): ROSETTA 2
References: UniProt: O75164, 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 , 5 types, 257 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-5UP / 2-(2-azanyl-1,3-thiazol-4-yl)pyridine-4-carboxamide


Mass: 220.251 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H8N4OS
#4: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 29 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 215 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.45 Å3/Da / Density % sol: 49.81 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Crystallisation solution is 0.1M Bis-Tris-Propane pH7.5, 12-16% PEG-4000. 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: ESRF / Beamline: ID23-2 / Wavelength: 0.8729 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Apr 11, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8729 Å / Relative weight: 1
ReflectionResolution: 2.6→49.48 Å / Num. obs: 47658 / % possible obs: 95.8 % / Redundancy: 3.1 % / Biso Wilson estimate: 60.4 Å2 / Rmerge(I) obs: 0.109 / Net I/σ(I): 7.5
Reflection shellResolution: 2.6→2.67 Å / Redundancy: 3 % / Rmerge(I) obs: 0.68 / Mean I/σ(I) obs: 1.4 / % possible all: 96.7

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OQ7

2oq7


Resolution: 2.6→49.48 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.8994 / SU R Cruickshank DPI: 1.099 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.832 / SU Rfree Blow DPI: 0.281 / SU Rfree Cruickshank DPI: 0.29
RfactorNum. reflection% reflectionSelection details
Rfree0.2256 2424 5.09 %RANDOM
Rwork0.1791 ---
obs0.1814 47648 95.69 %-
Displacement parametersBiso mean: 54.06 Å2
Baniso -1Baniso -2Baniso -3
1--0.8272 Å20 Å24.2195 Å2
2---1.5684 Å20 Å2
3---2.3956 Å2
Refine analyzeLuzzati coordinate error obs: 0.311 Å
Refinement stepCycle: 1 / Resolution: 2.6→49.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10984 0 188 215 11387
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111483HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0715580HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3688SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes236HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1741HARMONIC5
X-RAY DIFFRACTIONt_it11483HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.86
X-RAY DIFFRACTIONt_other_torsion18.89
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1467SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact13002SEMIHARMONIC4
LS refinement shellResolution: 2.6→2.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2767 168 4.77 %
Rwork0.2188 3356 -
all0.2216 3524 -
obs--97.31 %
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)
13.4090.9689-0.23814.18410.59822.1605-0.0168-0.12740.17230.1267-0.04610.37620.2845-0.46820.0629-0.15890.0173-0.0903-0.045-0.0742-0.26477.743146.5227-52.8235
21.0911-2.4981.35540.928-2.49221.9966-0.02750.0720.1361-0.12240.06910.0767-0.054-0.0464-0.04170.02620.0183-0.13390.027-0.015-0.02938.762359.5313-66.5526
32.99761.0942-0.01712.3772-0.28072.2501-0.0521-0.3253-0.15780.1642-0.0497-0.2980.3245-0.05580.1018-0.08690.0307-0.0445-0.1121-0.0871-0.140216.4744.2379-53.0735
4-0.8393-2.73422.2831.8549-1.27122.01330.0024-0.2443-0.31260.0326-0.0188-0.35530.1850.19110.01640.28340.08720.0659-0.23650.0902-0.006322.652423.0194-48.223
51.7614-0.0536-0.48513.2114-1.51123.53910.01520.0892-0.0908-0.520.0077-0.17260.55810.5534-0.0229-0.05810.0225-0.0188-0.087-0.042-0.20495.55781.6432-14.9516
63.3744-0.5701-1.30312.50290.35283.4554-0.03940.20850.5204-0.12560.0150.0564-0.09280.19450.02440.0315-0.109-0.0199-0.16070.0895-0.0966-0.412120.7815-13.7229
72.3886-0.0637-0.55231.9011-0.24462.92480.08550.3946-0.0486-0.28370.04650.25530.3558-0.1276-0.1320.00070.0111-0.0276-0.11480.0241-0.1581-4.85985.7343-14.5748
82.12052.4583-0.44821.93662.6662.4976-0.01950.3943-0.3765-0.26390.02140.35260.3855-0.2665-0.00190.1776-0.1247-0.1145-0.1765-0.0709-0.0873-12.3593-11.5755-19.1499
90.6923-0.6504-1.98884.2573-1.2908-0.42290.02820.05680.15710.0288-0.0969-0.2313-0.2464-0.07940.06870.1718-0.0750.0665-0.08620.0633-0.0972-12.1576-3.174-60.6624
102.16490.34030.86933.0615-1.1281.44780.1954-0.116-0.11940.0953-0.063-0.1324-0.04710.0158-0.13230.05310.02410.0239-0.0938-0.0225-0.238-16.2574-22.2472-53.7048
112.4117-2.9244-1.33460.0349-0.16513.8235-0.02890.1821-0.2084-0.27480.0996-0.10420.05490.093-0.07070.21660.0519-0.0657-0.1024-0.0275-0.106-17.2634-31.2122-68.8653
120.7641-1.9485-2.42240.0288-1.28012.8690.0073-0.2414-0.09360.149-0.0287-0.0225-0.11150.13240.02140.02490.1036-0.051-0.02920.0821-0.0933-16.4235-27.058-51.0718
132.7378-0.53670.93251.8632-0.75132.20760.0318-0.3220.16680.20330.13020.0869-0.2473-0.1903-0.16210.02990.05960.076-0.11790.0108-0.1736-23.5887-16.5084-55.1093
142.9825-3.16691.986201.25371.6673-0.047-0.48650.18950.29830.13780.2972-0.2327-0.3817-0.09070.20730.16430.2383-0.0796-0.0699-0.2353-31.0959-0.7617-46.5165
150.9593-1.2272-2.81083.1925-0.29481.30020.0180.06350.31580.1034-0.23230.2735-0.3614-0.28760.21430.02690.05790.0326-0.0921-0.0637-0.0379-32.469760.5588-13.4185
16-0.3213-0.85440.84911.5615-0.50491.062-0.03770.053-0.12270.0610.04040.1230.2353-0.0967-0.00270.0091-0.0373-0.0358-0.03750.0151-0.0087-32.606534.0278-19.4126
176.16020.75780.95693.03880.70671.5720.1491-0.2534-0.52860.0063-0.15890.19560.1528-0.17060.00970.0928-0.1022-0.0198-0.18930.0491-0.0535-26.935231.3876-8.6762
181.95950.3058-0.02811.54970.20632.1118-0.00750.21390.0453-0.1607-0.00460.10770.0151-0.33290.0121-0.0172-0.02950.0055-0.0699-0.0035-0.1213-25.473345.7448-19.1162
193.22750.5470.47510.9636-0.06042.03870.0975-0.096-0.06180.198-0.0872-0.0701-0.0259-0.003-0.01030.0602-0.0233-0.0092-0.1287-0.0298-0.098-19.633546.0723-11.8975
201.75031.43850.25340.5265-1.17483.6223-0.00720.51070.3151-0.04060.03450.0616-0.2980.2166-0.02730.0445-0.0342-0.0061-0.06480.0713-0.0979-14.240661.144-27.2846
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|9 - 101}
2X-RAY DIFFRACTION2{A|102 - 124}
3X-RAY DIFFRACTION3{A|125 - 317}
4X-RAY DIFFRACTION4{A|318 - 354}
5X-RAY DIFFRACTION5{B|3 - 78}
6X-RAY DIFFRACTION6{B|79 - 144}
7X-RAY DIFFRACTION7{B|145 - 293}
8X-RAY DIFFRACTION8{B|294 - 354}
9X-RAY DIFFRACTION9{C|6 - 26}
10X-RAY DIFFRACTION10{C|27 - 101}
11X-RAY DIFFRACTION11{C|102 - 124}
12X-RAY DIFFRACTION12{C|125 - 144}
13X-RAY DIFFRACTION13{C|145 - 293}
14X-RAY DIFFRACTION14{C|294 - 355}
15X-RAY DIFFRACTION15{D|6 - 53}
16X-RAY DIFFRACTION16{D|54 - 78}
17X-RAY DIFFRACTION17{D|79 - 124}
18X-RAY DIFFRACTION18{D|125 - 226}
19X-RAY DIFFRACTION19{D|227 - 293}
20X-RAY DIFFRACTION20{D|294 - 354}

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