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- PDB-5f37: Crystal structure of human KDM4A in complex with compound 58 -

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Basic information

Entry
Database: PDB / ID: 5f37
TitleCrystal structure of human KDM4A in complex with compound 58
ComponentsLysine-specific demethylase 4A
KeywordsOXIDOREDUCTASE / Epigenetics / Demethylase / Inhibitor
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
3H-pyrido[3,4-d]pyrimidin-4-one / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.22 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)171,59064
Polymers167,4184
Non-polymers4,17160
Water13,890771
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A: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,03418
Polymers41,8551
Non-polymers1,17917
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,08019
Polymers41,8551
Non-polymers1,22518
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,64512
Polymers41,8551
Non-polymers79111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,83115
Polymers41,8551
Non-polymers97714
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.330, 102.430, 142.460
Angle α, β, γ (deg.)90.00, 99.83, 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


Mass: 41854.617 Da / Num. of mol.: 4 / Fragment: UNP residues 1-359
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 BL21(DE3) (bacteria) / 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, 831 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-N5J / 3H-pyrido[3,4-d]pyrimidin-4-one


Mass: 147.134 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C7H5N3O
#4: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 43 / Source method: obtained synthetically / Formula: C2H6O2
#5: 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
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 771 / 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: 2.46 Å3/Da / Density % sol: 50.04 %
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: Diamond / Beamline: I04 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 1, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.22→48.21 Å / Num. obs: 78706 / % possible obs: 98.3 % / Redundancy: 3.3 % / Biso Wilson estimate: 40.33 Å2 / Rmerge(I) obs: 0.135 / Net I/σ(I): 6.9
Reflection shellResolution: 2.22→2.28 Å / Redundancy: 3.3 % / Mean I/σ(I) obs: 1 / % possible all: 98.7

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Processing

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

2oq7


Resolution: 2.22→48.21 Å / Cor.coef. Fo:Fc: 0.9516 / Cor.coef. Fo:Fc free: 0.9283 / SU R Cruickshank DPI: 0.24 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.244 / SU Rfree Blow DPI: 0.182 / SU Rfree Cruickshank DPI: 0.183
RfactorNum. reflection% reflectionSelection details
Rfree0.2088 3962 5.04 %RANDOM
Rwork0.1694 ---
obs0.1714 78676 98.16 %-
Displacement parametersBiso mean: 41.29 Å2
Baniso -1Baniso -2Baniso -3
1-1.2159 Å20 Å22.6427 Å2
2---0.5878 Å20 Å2
3----0.6281 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 2.22→48.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11148 0 244 771 12163
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111700HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0515838HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3771SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes229HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1766HARMONIC5
X-RAY DIFFRACTIONt_it11700HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.15
X-RAY DIFFRACTIONt_other_torsion17.04
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1489SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies7HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact13826SEMIHARMONIC4
LS refinement shellResolution: 2.22→2.28 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2503 301 5.19 %
Rwork0.2197 5498 -
all0.2213 5799 -
obs--98.43 %
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)
14.9578-0.47741.00765.22540.81912.5982-0.0027-0.1368-0.22260.01080.14990.17710.5239-0.494-0.1471-0.0413-0.103-0.044-0.0699-0.0072-0.066-7.8763-122.6313.4435
22.5942-0.3812-1.81141.3558-0.25843.4824-0.0987-0.27580.48140.0180.114-0.0475-0.2805-0.0309-0.0153-0.1730.0194-0.0429-0.1-0.15090.1263-0.1009-94.664619.9541
30.3697-1.9390.66321.5165-2.82762.6061-0.01880.22030.178-0.16370.01950.0898-0.1065-0.1525-0.0006-0.0850.0054-0.1262-0.11810.0070.1876-3.5693-95.49613.5505
41.60620.1430.07680.98170.0371.25290.0134-0.15140.19270.05020.0288-0.07250.0688-0.0363-0.0422-0.10430.0022-0.0254-0.049-0.0722-0.00073.5809-109.3315.7563
53.0563-1.4113-0.27411.0018-0.52212.8075-0.0528-0.6285-0.54690.17570.0193-0.52190.52920.43960.0335-0.06460.142-0.0665-0.07670.07090.019812.0833-126.94121.9002
61.1118-0.42330.01533.1342-1.38572.04520.12890.1482-0.0859-0.4201-0.142-0.16720.37020.51990.0131-0.08750.0123-0.0081-0.043-0.0564-0.1119-6.9847-153.77455.8835
70.83711.420.40712.08190.89112.654-0.00280.1190.21860.02790.06250.1318-0.54420.1166-0.0596-0.0717-0.00580.0423-0.09450.11720.1039-16.4366-131.49351.6648
80.9155-0.64782.65222.11912.84151.67520.004-0.15250.10280.3040.0796-0.0744-0.25780.2675-0.0836-0.0467-0.06110.0294-0.0895-0.00610.054-9.2861-132.19565.6921
91.4264-0.1298-0.01651.6465-0.42071.67140.09070.2028-0.0665-0.27940.05270.23660.21520.0041-0.1435-0.0561-0.0123-0.0528-0.1257-0.0267-0.048-18.6183-152.69953.971
103.2869-0.91280.77495.1503-1.18713.08360.00820.25530.5193-0.1101-0.048-0.2176-0.4060.18570.0398-0.02960.01160.0406-0.0909-0.0174-0.0313-24.7286-159.39411.8679
111.6465-0.05481.93121.60420.33992.20980.0647-0.2243-0.2151-0.01450.0551-0.06410.1559-0.2188-0.1199-0.04090.0024-0.0271-0.05510.0608-0.0368-29.3291-187.51918.3635
121.75972.26620.77460.1812-0.38613.55370.0240.3385-0.0646-0.38870.1124-0.14920.03970.0817-0.13640.03290.0626-0.0001-0.0471-0.06370.0285-28.6904-186.0511.282
131.9104-0.48010.33921.1556-0.48261.2757-0.0163-0.33630.08470.1910.1014-0.0106-0.1371-0.166-0.0851-0.02410.05090.0054-0.0177-0.0217-0.0926-32.4331-173.31718.5057
141.4689-0.2330.70321.7504-0.44281.1498-0.0174-0.2697-0.00080.09180.11780.2065-0.0744-0.2962-0.1004-0.05670.0620.0282-0.02590.0201-0.1082-39.7587-170.96714.2825
150.6999-2.26361.15113.03870.94921.8677-0.0948-0.33650.38930.49350.22180.3399-0.2874-0.4784-0.12690.08510.17570.0747-0.0249-0.1238-0.0508-42.0222-151.64723.7975
162.44170.48980.51343.35691.13851.7301-0.0262-0.12910.3476-0.0576-0.16510.3879-0.2234-0.3650.1913-0.10730.02150.003-0.04470.0392-0.0462-46.4913-100.81854.1426
173.83570.39351.93352.02130.36152.43080.0634-0.3049-0.42610.1671-0.08820.15120.1743-0.23030.0248-0.0579-0.05480.0234-0.15090.05540.0781-37.959-123.50861.3186
181.84880.0915-0.06450.66940.11291.0290.02020.0787-0.03180.0067-0.020.0318-0.0201-0.0942-0.0002-0.0609-0.0104-0.0184-0.07610.0285-0.0075-35.5952-109.08253.6004
190.75671.1784-0.09570-1.09672.08480.05930.3460.2235-0.15060.0280.0808-0.20730.104-0.0873-0.0042-0.012-0.0116-0.04350.04330.0188-26.3442-93.586642.8547
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|5 - 53}
2X-RAY DIFFRACTION2{A|54 - 101}
3X-RAY DIFFRACTION3{A|102 - 124}
4X-RAY DIFFRACTION4{A|125 - 293}
5X-RAY DIFFRACTION5{A|294 - 354}
6X-RAY DIFFRACTION6{B|1 - 78}
7X-RAY DIFFRACTION7{B|79 - 101}
8X-RAY DIFFRACTION8{B|102 - 124}
9X-RAY DIFFRACTION9{B|125 - 354}
10X-RAY DIFFRACTION10{C|7 - 53}
11X-RAY DIFFRACTION11{C|54 - 101}
12X-RAY DIFFRACTION12{C|102 - 124}
13X-RAY DIFFRACTION13{C|125 - 226}
14X-RAY DIFFRACTION14{C|227 - 317}
15X-RAY DIFFRACTION15{C|318 - 354}
16X-RAY DIFFRACTION16{D|6 - 70}
17X-RAY DIFFRACTION17{D|71 - 124}
18X-RAY DIFFRACTION18{D|125 - 293}
19X-RAY DIFFRACTION19{D|294 - 354}

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