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- PDB-6h4u: Crystal structure of human KDM4A in complex with compound 34b -

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Basic information

Entry
Database: PDB / ID: 6h4u
TitleCrystal structure of human KDM4A in complex with compound 34b
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 H4K20me2 reader activity / 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 H3]-trimethyl-L-lysine36 demethylase / histone H3K36me2/H3K36me3 demethylase activity / apoptotic chromosome condensation / histone H4K20me2 reader activity / 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 / 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-FO2 / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.21 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)169,90027
Polymers167,4184
Non-polymers2,48123
Water12,809711
1
A: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5017
Polymers41,8551
Non-polymers6476
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4887
Polymers41,8551
Non-polymers6336
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4887
Polymers41,8551
Non-polymers6336
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4236
Polymers41,8551
Non-polymers5695
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.966, 104.220, 145.035
Angle α, β, γ (deg.)90.00, 99.57, 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, 734 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-FO2 / 8-[4-(1-methylpiperidin-4-yl)pyrazol-1-yl]-3~{H}-pyrido[3,4-d]pyrimidin-4-one


Mass: 310.354 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H18N6O
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


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


Mass: 18.015 Da / Num. of mol.: 711 / 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: 2.62 Å3/Da / Density % sol: 53.14 %
Crystal growTemperature: 293 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: I04-1 / Wavelength: 0.9282 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 18, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9282 Å / Relative weight: 1
ReflectionResolution: 2.21→49.3 Å / Num. obs: 86644 / % possible obs: 100 % / Redundancy: 6.9 % / Biso Wilson estimate: 54.98 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.088 / Net I/σ(I): 11.7
Reflection shellResolution: 2.21→2.25 Å / Redundancy: 7 % / Rmerge(I) obs: 2.555 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 4589 / CC1/2: 0.306 / % 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: 2.21→49.3 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.95 / SU R Cruickshank DPI: 0.213 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.213 / SU Rfree Blow DPI: 0.168 / SU Rfree Cruickshank DPI: 0.169
RfactorNum. reflection% reflectionSelection details
Rfree0.208 4176 4.82 %RANDOM
Rwork0.176 ---
obs0.177 86605 100 %-
Displacement parametersBiso mean: 61.4 Å2
Baniso -1Baniso -2Baniso -3
1-1.9243 Å20 Å22.3298 Å2
2---4.2653 Å20 Å2
3---2.341 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: 1 / Resolution: 2.21→49.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10889 0 131 713 11733
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111452HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9915591HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3693SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes228HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1776HARMONIC5
X-RAY DIFFRACTIONt_it11452HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.8
X-RAY DIFFRACTIONt_other_torsion16.79
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1454SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies21HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact12005SEMIHARMONIC4
LS refinement shellResolution: 2.21→2.27 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2689 351 5.47 %
Rwork0.2377 6069 -
all0.2394 6420 -
obs--99.87 %
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)
10.65540.1269-1.35622.86840.42571.09530.0685-0.00730.3196-0.0248-0.08480.2929-0.4704-0.17980.0163-0.00430.0740.0027-0.0639-0.02070.0587-33.7775-5.6216-14.1847
21.5626-0.0140.19081.33520.17491.59170.06270.0467-0.04880.0528-0.06630.16980.037-0.15480.0036-0.0811-0.0481-0.0073-0.07130.0089-0.0672-25.6738-24.7998-14.8778
31.5481.4255-0.0130.2236-2.1525.1420.11070.31380.1937-0.027-0.1904-0.0477-0.43530.31720.07970.0209-0.058-0.0196-0.08020.0527-0.054-15.1102-6.0117-28.1028
42.05251.7756-1.5534.4275-1.28151.70580.06570.02860.29270.05330.0316-0.097-0.5190.2836-0.09730.0622-0.00480.1237-0.17960.04240.0255-14.020131.155-60.129
52.32560.52360.33463.3579-0.98422.01370.2005-0.1457-0.00570.0794-0.0853-0.2367-0.07340.1654-0.1152-0.11770.08720.0403-0.11430.0202-0.1484-18.09187.5201-55.3006
61.6092-0.0169-0.83341.1275-0.546-0.32680.0654-0.13870.00250.27580.02140.2067-0.16480.0047-0.08680.03760.07990.0617-0.00480.0422-0.0736-23.31413.8484-50.8537
71.79280.38990.28072.3922-0.67712.25480.1617-0.0960.45430.19670.11170.371-0.2928-0.3224-0.2734-0.04160.08870.1293-0.10930.0716-0.0354-28.23319.2573-58.9042
80.6123-3.3174-1.13575.28922.23842.7339-0.0413-0.22920.29620.17580.03760.2438-0.118-0.20220.00370.21490.16730.2226-0.2701-0.0844-0.1406-32.290537.0424-46.953
92.2243-1.3390.99745.2259-0.91980.27310.04430.1424-0.2719-0.08590.0446-0.09780.18570.1066-0.08890.04190.06310.0184-0.0136-0.0594-0.09748.089229.5822-9.8128
101.7303-0.75060.22652.7981-0.05692.8688-0.00660.40670.0193-0.11790.1473-0.32690.4140.6205-0.1407-0.12510.02370.03990.0787-0.0225-0.14437.353538.7692-18.8883
115.6039-0.3422-1.52132.3888-0.55695.0921-0.04310.14970.5170.10510.0803-0.1555-0.54560.2066-0.0371-0.0597-0.0894-0.0133-0.18070.0799-0.0111-2.256959.2126-11.1868
122.405-0.286-0.07362.2097-0.4092.164-0.06860.355-0.068-0.27640.09160.16640.29570.0715-0.0231-0.0649-0.0413-0.0197-0.07650.0312-0.1541-4.317343.2455-14.8983
131.04792.3979-1.17760.86083.28361.9198-0.05410.3433-0.36-0.31480.03430.35280.3661-0.33630.01970.155-0.1406-0.1274-0.1542-0.0803-0.0381-13.563624.9121-20.0325
141.7671-0.16470.16233.57960.50222.8983-0.1047-0.2645-0.24170.08450.09420.33580.513-0.59510.0105-0.1481-0.1190.01830.0118-0.0961-0.0872-55.8325-28.8091-53.3532
154.27640.0738-1.38972.74680.46252.9337-0.02240.19630.5273-0.35860.07970.2158-0.3363-0.2452-0.0573-0.1220.0992-0.0924-0.1163-0.03830.0456-45.7267-6.6596-61.134
162.53070.52550.29811.55310.13771.81030.0224-0.3018-0.05240.1331-0.12140.0060.2673-0.27610.099-0.10450.0217-0.0279-0.027-0.0811-0.0768-44.9269-22.057-51.9138
172.69971.3963-0.48022.5289-0.06872.6475-0.09290.0711-0.1466-0.0497-0.0861-0.29030.2874-0.06680.1789-0.07660.0503-0.0336-0.0861-0.0666-0.0693-40.7262-22.2099-60.2633
183.1566-1.13570.06670.006-2.75081.4798-0.0505-0.1518-0.03940.1002-0.0616-0.0850.18180.03260.1121-0.03860.1446-0.0432-0.07890.05620.1055-31.9862-31.5171-47.8461
19-0.5062-2.61561.40993.549-1.79531.0953-0.0078-0.1532-0.22460.0843-0.0507-0.14890.15560.12690.05850.16830.13510.055-0.21050.10590.029-35.4796-44.565-48.1929
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|8 - 36}
2X-RAY DIFFRACTION2{A|37 - 293}
3X-RAY DIFFRACTION3{A|294 - 353}
4X-RAY DIFFRACTION4{B|6 - 53}
5X-RAY DIFFRACTION5{B|54 - 162}
6X-RAY DIFFRACTION6{B|163 - 190}
7X-RAY DIFFRACTION7{B|191 - 311}
8X-RAY DIFFRACTION8{B|312 - 353}
9X-RAY DIFFRACTION9{C|6 - 26}
10X-RAY DIFFRACTION10{C|27 - 70}
11X-RAY DIFFRACTION11{C|71 - 124}
12X-RAY DIFFRACTION12{C|125 - 293}
13X-RAY DIFFRACTION13{C|294 - 354}
14X-RAY DIFFRACTION14{D|10 - 70}
15X-RAY DIFFRACTION15{D|71 - 124}
16X-RAY DIFFRACTION16{D|125 - 226}
17X-RAY DIFFRACTION17{D|227 - 293}
18X-RAY DIFFRACTION18{D|294 - 317}
19X-RAY DIFFRACTION19{D|318 - 354}

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