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- PDB-5f3g: Crystal structure of human KDM4A in complex with compound 53a -

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Basic information

Entry
Database: PDB / ID: 5f3g
TitleCrystal structure of human KDM4A in complex with compound 53a
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
Chem-5UL / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsLe Bihan, Y.-V. / 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 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)170,32024
Polymers167,4184
Non-polymers2,90120
Water6,539363
1
A: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5916
Polymers41,8551
Non-polymers7365
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4344
Polymers41,8551
Non-polymers5803
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6697
Polymers41,8551
Non-polymers8146
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6267
Polymers41,8551
Non-polymers7716
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.267, 100.567, 142.592
Angle α, β, γ (deg.)90.00, 99.43, 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 / Plasmid: pNIC28 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta2
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, 383 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-5UL / 8-[4-[2-[4-[(4-chlorophenyl)methyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3~{H}-pyrido[3,4-d]pyrimidin-4-one


Mass: 448.948 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H25ClN6O
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 363 / 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: 2.42 Å3/Da / Density % sol: 49.16 %
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: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.5419 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: May 3, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5419 Å / Relative weight: 1
ReflectionResolution: 2.5→48.06 Å / Num. obs: 54102 / % possible obs: 97.5 % / Redundancy: 13.9 % / Biso Wilson estimate: 52.41 Å2 / Rmerge(I) obs: 0.195 / Net I/σ(I): 11.1
Reflection shellResolution: 2.5→2.56 Å / Redundancy: 9.2 % / Mean I/σ(I) obs: 1.2 / % possible all: 79.6

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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: 2.5→42.5 Å / Cor.coef. Fo:Fc: 0.9079 / Cor.coef. Fo:Fc free: 0.8693 / SU R Cruickshank DPI: 0.556 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.526 / SU Rfree Blow DPI: 0.275 / SU Rfree Cruickshank DPI: 0.281
RfactorNum. reflection% reflectionSelection details
Rfree0.2464 2576 4.77 %RANDOM
Rwork0.2027 ---
obs0.2048 53976 97.65 %-
Displacement parametersBiso mean: 53.42 Å2
Baniso -1Baniso -2Baniso -3
1-6.8059 Å20 Å2-1.1386 Å2
2--4.5491 Å20 Å2
3----11.355 Å2
Refine analyzeLuzzati coordinate error obs: 0.362 Å
Refinement stepCycle: 1 / Resolution: 2.5→42.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10661 0 131 363 11155
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111131HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0815166HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3527SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes213HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1734HARMONIC5
X-RAY DIFFRACTIONt_it11131HARMONIC20
X-RAY DIFFRACTIONt_nbd7SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.91
X-RAY DIFFRACTIONt_other_torsion18.92
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1416SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies5HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact12857SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.56 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3313 171 5.13 %
Rwork0.2861 3165 -
all0.2884 3336 -
obs--82.77 %
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)
1-0.22621.32590.47146.2971.09372.64020.0289-0.07990.14340.1295-0.07550.2-0.4132-0.35080.0467-0.0450.08560.06820.0947-0.029-0.0743-32.94882.7704-13.5694
22.4482-0.13020.54992.3187-0.06472.05670.0819-0.095-0.05170.0139-0.03480.20950.0781-0.1346-0.0471-0.1923-0.0461-0.01720.0377-0.0222-0.148-24.5819-15.9176-14.5617
32.05220.5652-1.46360.4211-1.4374.15160.130.1093-0.0179-0.1247-0.0998-0.1614-0.51860.3029-0.0302-0.0313-0.0541-0.04210.04970.0406-0.1229-16.63142.7435-26.3466
40.835-0.47822.10171.2567-1.33610.6751-0.02580.023-0.30180.02670.12650.05550.2668-0.1582-0.10070.0128-0.14390.06180.1166-0.0612-0.1286-7.2258-14.190512.2756
51.92350.354-0.34385.161-0.6551-0.0392-0.0993-0.28960.16990.29420.22170.4036-0.0205-0.3949-0.1224-0.1610.0002-0.01820.1553-0.0868-0.2307-3.78464.058318.0535
66.21612.0267-1.38863.89430.67553.0419-0.11110.14970.4435-0.04980.27110.2156-0.1638-0.2756-0.16-0.07330.1492-0.0836-0.06830.0132-0.06260.760115.63911.3441
73.52550.7274-0.67254.69060.15542.9599-0.2844-0.2415-0.20870.47890.2692-0.3130.4199-0.14440.0153-0.18330.0545-0.07220.0183-0.0503-0.27044.34260.361214.4299
84.1051-2.6852.50170.0074-1.59711.3334-0.103-0.1219-0.17040.24590.061-0.18740.44610.15790.042-0.00570.1465-0.1016-0.20230.04530.203713.4689-17.936920.2124
9-0.58391.56121.40178.2722.28287.20930.09250.09970.2227-0.0863-0.01160.223-0.4543-0.173-0.08090.06070.14650.1395-0.20130.0205-0.0011-44.4884-10.369858.9415
104.90060.56430.55654.87370.20561.74970.1026-0.1196-0.27010.3340.05720.19040.4099-0.5716-0.1598-0.1306-0.0974-0.0878-0.17960.0257-0.0631-39.352-37.979557.9298
112.71020.5492-0.55142.9570.04312.7850.1860.19420.2282-0.21780.0102-0.2038-0.2674-0.1547-0.1962-0.05830.00440.0471-0.1643-0.0123-0.0758-34.1184-24.404456.1832
123.28413.03390.11845.4869-0.87014.1501-0.05270.3750.4148-0.24560.1725-0.0515-0.29370.4991-0.11980.2049-0.13350.2197-0.28850.0733-0.1413-25.9384-6.453646.9781
13-0.5003-1.39072.30865.37711.72610.78070.03530.0405-0.4442-0.1423-0.0309-0.13810.1860.2063-0.0044-0.03270.1435-0.04110.06610.058-0.061-3.111923.920455.0998
143.4428-0.9849-0.82133.00140.2941.8245-0.02570.45740.5582-0.18390.0995-0.2607-0.16280.4939-0.0738-0.2032-0.0743-0.1646-0.02740.1205-0.0381-9.737646.418451.8842
154.09540.64011.68214.2751-1.57954.4849-0.09140.12680.5070.3547-0.0742-0.2847-0.1580.33860.1655-0.2472-0.0264-0.2136-0.22520.07790.2426-9.239149.849258.9077
163.9301-0.65190.32684.1605-0.22481.60530.02050.5111-0.0984-0.3623-0.0263-0.07970.35460.24420.0058-0.1224-0.0051-0.0933-0.06740.0841-0.1357-14.597435.827151.4664
175.4731-1.9355-0.61442.5320.23614.5524-0.1092-0.14050.2090.2833-0.05360.31860.5096-0.14060.1628-0.1082-0.0367-0.0951-0.16350.0668-0.0141-17.736138.053159.0537
184.25342.56680.12132.79862.292.1991-0.04090.4216-0.3071-0.15430.03460.40680.2824-0.07860.0064-0.0503-0.125-0.1347-0.2814-0.17480.2519-23.768619.679847.8395
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|8 - 53}
2X-RAY DIFFRACTION2{A|54 - 283}
3X-RAY DIFFRACTION3{A|284 - 354}
4X-RAY DIFFRACTION4{B|9 - 37}
5X-RAY DIFFRACTION5{B|38 - 78}
6X-RAY DIFFRACTION6{B|79 - 124}
7X-RAY DIFFRACTION7{B|125 - 293}
8X-RAY DIFFRACTION8{B|294 - 353}
9X-RAY DIFFRACTION9{C|8 - 53}
10X-RAY DIFFRACTION10{C|54 - 124}
11X-RAY DIFFRACTION11{C|125 - 291}
12X-RAY DIFFRACTION12{C|292 - 354}
13X-RAY DIFFRACTION13{D|11 - 36}
14X-RAY DIFFRACTION14{D|37 - 102}
15X-RAY DIFFRACTION15{D|103 - 144}
16X-RAY DIFFRACTION16{D|145 - 226}
17X-RAY DIFFRACTION17{D|227 - 293}
18X-RAY DIFFRACTION18{D|294 - 354}

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