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- PDB-6h4o: Crystal structure of human KDM4A in complex with compound 18a -

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Basic information

Entry
Database: PDB / ID: 6h4o
TitleCrystal structure of human KDM4A in complex with compound 18a
ComponentsLysine-specific demethylase 4A
KeywordsOXIDOREDUCTASE / Histone demethylase / Inhibitor / transcription
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 H3]-trimethyl-L-lysine9 demethylase / histone H3K9me2/H3K9me3 demethylase activity / 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 H3]-trimethyl-L-lysine9 demethylase / histone H3K9me2/H3K9me3 demethylase activity / 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 / positive regulation of neuron differentiation / methylated histone binding / 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 / positive regulation of gene expression / chromatin / 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-finger / 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-FQH / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsLe Bihan, Y.V. / 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 ...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)170,30523
Polymers167,4184
Non-polymers2,88719
Water8,413467
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A: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5816
Polymers41,8551
Non-polymers7275
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5465
Polymers41,8551
Non-polymers6914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6467
Polymers41,8551
Non-polymers7916
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5325
Polymers41,8551
Non-polymers6774
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.516, 101.374, 142.544
Angle α, β, γ (deg.)90.00, 99.50, 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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM4A, JHDM3A, JMJD2, JMJD2A, KIAA0677 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta
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 , 6 types, 486 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-FQH / 8-[4-[2-[4-[3-(trifluoromethyl)phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3~{H}-pyrido[3,4-d]pyrimidin-4-one


Mass: 468.474 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H23F3N6O
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 467 / 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: 2.45 Å3/Da / Density % sol: 49.76 %
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: I02 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 17, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.25→48.95 Å / Num. obs: 76575 / % possible obs: 99.9 % / Redundancy: 6.6 % / Biso Wilson estimate: 54.23 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.128 / Net I/σ(I): 10
Reflection shellResolution: 2.25→2.3 Å / Redundancy: 6.6 % / Rmerge(I) obs: 1.874 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 4568 / CC1/2: 0.357 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OQ7

2oq7


Resolution: 2.25→48.95 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.945 / SU R Cruickshank DPI: 0.226 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.221 / SU Rfree Blow DPI: 0.171 / SU Rfree Cruickshank DPI: 0.174
RfactorNum. reflection% reflectionSelection details
Rfree0.203 3826 5 %RANDOM
Rwork0.169 ---
obs0.171 76551 99.9 %-
Displacement parametersBiso mean: 59.64 Å2
Baniso -1Baniso -2Baniso -3
1-4.4653 Å20 Å23.2659 Å2
2---2.6801 Å20 Å2
3----1.7852 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: 1 / Resolution: 2.25→48.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10569 0 139 468 11176
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111111HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0415155HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3492SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes203HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1747HARMONIC5
X-RAY DIFFRACTIONt_it11111HARMONIC20
X-RAY DIFFRACTIONt_nbd6SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.13
X-RAY DIFFRACTIONt_other_torsion17.87
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1421SEMIHARMONIC5
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_contact12915SEMIHARMONIC4
LS refinement shellResolution: 2.25→2.31 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2408 300 5.3 %
Rwork0.2096 5361 -
all0.2112 5661 -
obs--100 %
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)
12.02952.3695-2.43925.8156-1.0788-0.2250.01280.0520.3534-0.0549-0.1228-0.2949-0.44990.15890.110.086-0.01630.1664-0.16820.02340.029715.95442.4182-58.4612
22.09360.24370.4833.9137-0.78151.83380.2662-0.1613-0.13470.1841-0.1319-0.32290.02720.1634-0.1343-0.0420.0580.078-0.10580.0191-0.151911.7629-20.7753-53.7804
32.1882-0.01420.20072.5616-0.32412.03920.1162-0.06880.0880.06620.02350.0846-0.1379-0.0321-0.1397-0.04080.04780.1087-0.13340.0394-0.1516.398-14.9635-57.8356
46.6009-1.8601-1.97775.18490.64063.7995-0.0102-0.47550.37770.3561-0.01040.1933-0.4908-0.38670.02060.12660.17070.2127-0.1502-0.0994-0.1753-2.67434.18-46.9349
51.7936-0.02560.31591.85940.01841.63530.0634-0.0218-0.0154-0.0218-0.07220.1601-0.0258-0.12160.0088-0.0613-0.02630.0467-0.10030.0016-0.11422.5755-52.0179-14.4124
62.78571.4711-0.87822.3106-2.58127.0270.0620.26560.1896-0.0388-0.26430.05-0.43880.58690.20230.0294-0.05720.0123-0.10160.0831-0.131214.0808-34.5208-27.2562
72.41111.15892.62386.0037-1.21192.65670.0317-0.2526-0.43830.10960.11330.31360.5644-0.528-0.1450.0001-0.14580.032-0.0536-0.0425-0.0676-25.1541-63.895-55.7514
86.38360.1988-2.89372.30650.49585.467-0.0079-0.22740.5515-0.03350.03920.2362-0.4238-0.3975-0.0313-0.14490.1-0.0393-0.2305-0.07230.0096-18.0628-37.0091-55.7091
93.44260.9021-0.64513.2361-0.07162.2371-0.1145-0.24010.00420.1562-0.0138-0.25610.2842-0.12470.1283-0.11760.0314-0.006-0.1078-0.0814-0.1561-13.4249-50.9865-54.4426
101.8513-2.67070.22010.888-1.65163.4112-0.0753-0.3499-0.31170.09860.0379-0.32150.40270.14340.03740.15220.13820.0013-0.20170.09520.0073-4.7308-69.4545-47.8581
113.9673-1.41912.16025.5518-0.02342.52980.070.3792-0.4491-0.16530.1553-0.26350.58280.4828-0.22540.03670.12840.0699-0.1228-0.0289-0.116335.5781-1.4684-11.554
122.2866-1.1384-0.80483.6529-0.37253.5332-0.10250.30570.2908-0.4256-0.017-0.1396-0.19030.36840.1195-0.0326-0.12970.0519-0.02470.1321-0.145630.569823.6708-22.1711
138.2517-0.311-2.66123.3961-1.55886.5305-0.0254-0.03660.54480.18450.0895-0.2087-0.52970.2843-0.0641-0.0572-0.05740.0135-0.24690.0082-0.020628.280427.3161-11.0824
142.4219-0.1868-0.47463.2674-0.28642.2558-0.13170.2013-0.0413-0.28740.18840.29660.21450.0252-0.0567-0.0552-0.030.0004-0.09280.0504-0.160324.63112.2183-14.5373
153.62982.65120.21291.69681.66812.9208-0.07790.3147-0.5317-0.40590.06410.37440.5169-0.31760.01380.1966-0.1417-0.0413-0.2531-0.0742-0.01815.6889-6.6069-19.4151
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|8 - 36}
2X-RAY DIFFRACTION2{A|37 - 101}
3X-RAY DIFFRACTION3{A|102 - 291}
4X-RAY DIFFRACTION4{A|292 - 354}
5X-RAY DIFFRACTION5{B|7 - 293}
6X-RAY DIFFRACTION6{B|294 - 354}
7X-RAY DIFFRACTION7{C|11 - 53}
8X-RAY DIFFRACTION8{C|54 - 124}
9X-RAY DIFFRACTION9{C|125 - 293}
10X-RAY DIFFRACTION10{C|294 - 354}
11X-RAY DIFFRACTION11{D|4 - 53}
12X-RAY DIFFRACTION12{D|54 - 78}
13X-RAY DIFFRACTION13{D|79 - 124}
14X-RAY DIFFRACTION14{D|125 - 293}
15X-RAY DIFFRACTION15{D|294 - 354}

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