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- PDB-6h4t: Crystal structure of human KDM4A in complex with compound 19a -

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Basic information

Entry
Database: PDB / ID: 6h4t
TitleCrystal structure of human KDM4A in complex with compound 19a
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-FOW / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.38 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_alt_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_alt_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.pdbx_ptnr2_label_alt_id / _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)170,35127
Polymers167,4184
Non-polymers2,93223
Water13,493749
1
A: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4475
Polymers41,8551
Non-polymers5934
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6968
Polymers41,8551
Non-polymers8417
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5266
Polymers41,8551
Non-polymers6715
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6828
Polymers41,8551
Non-polymers8277
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.860, 101.812, 142.680
Angle α, β, γ (deg.)90.00, 99.20, 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, 772 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-FOW / 8-[4-(2-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylethyl)pyrazol-1-yl]-3~{H}-pyrido[3,4-d]pyrimidin-4-one


Mass: 426.514 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H26N6O
#4: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 749 / 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: 2.48 Å3/Da / Density % sol: 50.36 %
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: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.5419 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Mar 18, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5419 Å / Relative weight: 1
ReflectionResolution: 2.38→47.87 Å / Num. obs: 65581 / % possible obs: 100 % / Redundancy: 14.7 % / Biso Wilson estimate: 50.02 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.262 / Net I/σ(I): 9.5
Reflection shellResolution: 2.38→2.44 Å / Redundancy: 11.9 % / Rmerge(I) obs: 3.66 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 4581 / CC1/2: 0.32 / % 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: 2.38→43.64 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.922 / SU R Cruickshank DPI: 0.324 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.333 / SU Rfree Blow DPI: 0.215 / SU Rfree Cruickshank DPI: 0.217
RfactorNum. reflection% reflectionSelection details
Rfree0.216 3335 5.09 %RANDOM
Rwork0.173 ---
obs0.176 65541 100 %-
Displacement parametersBiso mean: 50.53 Å2
Baniso -1Baniso -2Baniso -3
1-5.6629 Å20 Å2-1.5005 Å2
2---0.3389 Å20 Å2
3----5.324 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: 1 / Resolution: 2.38→43.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10744 0 170 751 11665
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111287HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0715380HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3623SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes223HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1769HARMONIC5
X-RAY DIFFRACTIONt_it11287HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.25
X-RAY DIFFRACTIONt_other_torsion17.25
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1427SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies14HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact13345SEMIHARMONIC4
LS refinement shellResolution: 2.38→2.44 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2547 269 5.6 %
Rwork0.2343 4538 -
all0.2354 4807 -
obs--99.96 %
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)
11.8479-0.24250.27036.21481.98812.38550.11270.06660.2506-0.2361-0.10270.4885-0.5241-0.3054-0.010.00830.0240.1323-0.1321-0.0316-0.0889-34.2122-5.9182-14.6968
23.96660.51421.49683.371.5122.25550.167-0.2545-0.32850.435-0.0875-0.06660.2885-0.063-0.07950.0124-0.0892-0.0131-0.1143-0.0054-0.0894-24.717-28.5122-9.0655
32.27020.3222-0.39472.13350.69371.4360.10870.08950.2541-0.10980.0628-0.0242-0.22990.0498-0.1715-0.0099-0.05080.0721-0.123-0.051-0.1012-22.6875-13.6575-14.3956
44.19363.01640.0263.5434-0.57172.50430.03480.46130.2667-0.3970.0936-0.2511-0.37590.2704-0.12840.1981-0.16990.214-0.21370.0982-0.1257-14.37853.4836-23.6034
52.1263-2.2309-1.0183.6587-1.04230.34160.03250.13210.5429-0.0869-0.0429-0.2458-0.45450.22150.01050.0461-0.06160.0534-0.0860.0232-0.0055-14.6306-36.4123-56.9661
62.35260.49370.24781.82810.01971.7570.0549-0.073-0.2547-0.0394-0.0841-0.30910.15130.24740.0292-0.08290.0758-0.0089-0.1170.0157-0.0597-16.0516-60.0338-54.7872
71.6810.35580.02371.20220.13661.73120.0457-0.02060.0651-0.0189-0.0458-0.0424-0.1025-0.07510.0001-0.00120.029-0.0085-0.0903-0.0096-0.0449-25.5769-51.1333-56.9318
82.311-2.1338-0.8110.00291.22334.79420.1069-0.29950.17670.0049-0.10990.0396-0.3018-0.35750.0030.08020.03290.0066-0.1156-0.077-0.0645-31.2642-35.8223-42.9649
9-0.249-1.61822.85663.7831.98950.9319-0.0277-0.1021-0.271-0.21460.04-0.26850.44780.0617-0.01220.13370.14130.0089-0.05540.0546-0.12498.3527-66.2613-14.6146
103.11710.2642-1.42453.8559-0.7312.6355-0.0560.19840.4943-0.22420.1005-0.22130.06490.2462-0.0444-0.1454-0.0779-0.1116-0.05530.1109-0.14432.2338-43.3665-18.2023
115.1578-0.0729-0.75284.2306-1.58953.4858-0.0767-0.10270.52640.0839-0.0143-0.1947-0.09990.33280.091-0.1756-0.0887-0.1343-0.13270.09670.02942.3331-39.9329-11.1537
123.96270.0768-1.25254.0671-1.01543.1139-0.23280.2823-0.0828-0.44250.17070.31420.5073-0.09080.0621-0.1042-0.0438-0.0901-0.13260.0907-0.1847-4.2195-53.087-14.9737
130.64672.6241-0.14260.00261.98231.8167-0.11210.4282-0.3-0.2922-0.00080.3530.5025-0.16350.11290.2629-0.1458-0.1047-0.1967-0.0502-0.0707-12.1758-69.9269-22.6713
143.22530.97321.16646.81491.71231.45150.0044-0.2459-0.4270.18110.08870.21490.5606-0.3633-0.09310.0671-0.08860.0015-0.0970.0403-0.1379-53.0825-1.4377-59.0024
152.98670.6676-1.19343.33080.31444.3633-0.0251-0.41280.47710.32870.01560.1923-0.3496-0.33820.0094-0.13910.0932-0.0069-0.0918-0.116-0.1121-46.909324.9315-54.3066
162.7489-0.5669-0.62082.45190.54182.4988-0.1188-0.3343-0.07210.22690.1557-0.19880.28760.063-0.0369-0.0510.0224-0.0334-0.0823-0.0568-0.1365-41.472410.9657-56.9698
172.8383-2.6649-1.69971.2784-1.75023.1563-0.0819-0.3332-0.55180.37580.1099-0.39730.52120.4822-0.0280.17660.1386-0.101-0.2430.0946-0.0185-33.2028-6.6017-50.8355
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|7 - 70}
2X-RAY DIFFRACTION2{A|71 - 124}
3X-RAY DIFFRACTION3{A|125 - 293}
4X-RAY DIFFRACTION4{A|294 - 354}
5X-RAY DIFFRACTION5{B|8 - 48}
6X-RAY DIFFRACTION6{B|49 - 159}
7X-RAY DIFFRACTION7{B|160 - 293}
8X-RAY DIFFRACTION8{B|294 - 354}
9X-RAY DIFFRACTION9{C|10 - 36}
10X-RAY DIFFRACTION10{C|37 - 102}
11X-RAY DIFFRACTION11{C|103 - 144}
12X-RAY DIFFRACTION12{C|145 - 293}
13X-RAY DIFFRACTION13{C|294 - 354}
14X-RAY DIFFRACTION14{D|5 - 53}
15X-RAY DIFFRACTION15{D|54 - 144}
16X-RAY DIFFRACTION16{D|145 - 293}
17X-RAY DIFFRACTION17{D|294 - 354}

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