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- PDB-5f2s: Crystal structure of human KDM4A in complex with compound 15 -

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Basic information

Entry
Database: PDB / ID: 5f2s
TitleCrystal structure of human KDM4A in complex with compound 15
ComponentsLysine-specific demethylase 4A
KeywordsOXIDOREDUCTASE / Epigenetics / Demethylase / Inhibitor
Function / homology
Function and homology information


[histone H3]-trimethyl-L-lysine36 demethylase / histone H3-tri/dimethyl-lysine-36 demethylase activity / histone demethylation / histone H3-K36 demethylation / histone H3-methyl-lysine-36 demethylase activity / cardiac muscle hypertrophy in response to stress / histone H3-tri/dimethyl-lysine-9 demethylase activity / [histone H3]-trimethyl-L-lysine9 demethylase / negative regulation of histone H3-K9 trimethylation / histone H3-K9 demethylation ...[histone H3]-trimethyl-L-lysine36 demethylase / histone H3-tri/dimethyl-lysine-36 demethylase activity / histone demethylation / histone H3-K36 demethylation / histone H3-methyl-lysine-36 demethylase activity / cardiac muscle hypertrophy in response to stress / histone H3-tri/dimethyl-lysine-9 demethylase activity / [histone H3]-trimethyl-L-lysine9 demethylase / negative regulation of histone H3-K9 trimethylation / histone H3-K9 demethylation / histone H3-methyl-lysine-9 demethylase activity / negative regulation of astrocyte differentiation / pericentric heterochromatin / histone demethylase activity / negative regulation of cell death / negative regulation of autophagy / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / methylated histone binding / positive regulation of neuron differentiation / response to nutrient levels / HDMs demethylate histones / fibrillar center / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromatin remodeling / negative regulation of gene expression / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / positive regulation of gene expression / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Jumonji domain-containing protein 2A Tudor domain / Lysine-specific demethylase 4, Tudor domain / Tudor domain / Tudor domain / JmjN domain profile. / jmjN domain / JmjN domain / Small domain found in the jumonji family of transcription factors / Extended PHD (ePHD) domain / Extended PHD (ePHD) domain profile. ...Jumonji domain-containing protein 2A Tudor domain / Lysine-specific demethylase 4, Tudor domain / Tudor domain / Tudor domain / JmjN domain profile. / jmjN domain / JmjN domain / 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-5TZ / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.08 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

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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)171,47158
Polymers167,4184
Non-polymers4,05354
Water16,916939
1
A: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,79713
Polymers41,8551
Non-polymers94312
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,88915
Polymers41,8551
Non-polymers1,03514
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,84314
Polymers41,8551
Non-polymers98913
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,94116
Polymers41,8551
Non-polymers1,08615
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.450, 102.320, 142.250
Angle α, β, γ (deg.)90.00, 99.82, 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 , 6 types, 993 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-5TZ / 2-(2-azanyl-1,3-thiazol-4-yl)pyridine-4-carboxylic acid


Mass: 221.236 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H7N3O2S
#4: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 37 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-CL / CHLORIDE ION / Chloride


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


Mass: 18.015 Da / Num. of mol.: 939 / 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: 2.54 Å3/Da / Density % sol: 51.61 %
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: Feb 27, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.08→57.82 Å / Num. obs: 95776 / % possible obs: 98.5 % / Redundancy: 3.3 % / Biso Wilson estimate: 34.41 Å2 / Rmerge(I) obs: 0.058 / Net I/σ(I): 11.8
Reflection shellResolution: 2.08→2.13 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.487 / Mean I/σ(I) obs: 2.3 / % possible all: 98.9

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OQ7
Resolution: 2.08→56.61 Å / Cor.coef. Fo:Fc: 0.9585 / Cor.coef. Fo:Fc free: 0.9509 / SU R Cruickshank DPI: 0.175 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.18 / SU Rfree Blow DPI: 0.143 / SU Rfree Cruickshank DPI: 0.143
RfactorNum. reflection% reflectionSelection details
Rfree0.191 4799 5.01 %RANDOM
Rwork0.1631 ---
obs0.1645 95754 98.36 %-
Displacement parametersBiso mean: 39.24 Å2
Baniso -1Baniso -2Baniso -3
1-0.1814 Å20 Å21.8418 Å2
2---0.6254 Å20 Å2
3---0.4441 Å2
Refine analyzeLuzzati coordinate error obs: 0.209 Å
Refinement stepCycle: LAST / Resolution: 2.08→56.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11140 0 233 939 12312
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111686HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9815827HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3804SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes231HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1773HARMONIC5
X-RAY DIFFRACTIONt_it11686HARMONIC20
X-RAY DIFFRACTIONt_nbd4SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.35
X-RAY DIFFRACTIONt_other_torsion16.38
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1480SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies11HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact13970SEMIHARMONIC4
LS refinement shellResolution: 2.08→2.13 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2348 379 5.3 %
Rwork0.1942 6773 -
all0.1964 7152 -
obs--98.92 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
12.0387-0.248-0.20761.944-0.09071.6727-0.11710.02360.1114-0.03310.1447-0.12220.18330.2374-0.0276-0.128-0.0072-0.0656-0.0560.0359-0.108720.7786-108.04853.0193
21.04682.37170.41251.36242.57431.531-0.0366-0.26260.11030.17680.06780.0018-0.09650.224-0.0311-0.0491-0.0016-0.1245-0.0107-0.02440.055419.7798-96.419367.347
32.3691-0.57850.3481.4808-0.22210.6641-0.12840.24690.3952-0.2133-0.0377-0.0097-0.00510.21950.1661-0.061-0.0463-0.0541-0.03840.08880.076717.777-99.693850.1854
41.5878-0.72880.01861.2870.28911.2557-0.04370.0667-0.0716-0.0863-0.01430.16520.18150.07310.058-0.0711-0.0074-0.0285-0.03640.0593-0.039613.7922-111.88450.87
51.7672-0.3803-0.66780.536-1.1081.3596-0.04670.05460.01670.14370.02930.3570.0698-0.15480.0174-0.05350.00540.0184-0.01180.04010.08060.4689-106.89861.7126
61.8872-1.0407-0.03751.41670.77812.0799-0.1338-0.09610.06040.08730.08010.1250.18670.18490.0537-0.06660.0167-0.024-0.04230.0489-0.061316.6136-111.14457.8088
72.98861.78710.13581.33471.17482.7852-0.09120.2611-0.4626-0.0668-0.08250.4940.4848-0.26150.17370.0246-0.1466-0.0276-0.1737-0.03610.08715.0611-128.26748.1756
81.85820.13341.01583.31041.24111.2130.1362-0.0565-0.43320.1281-0.04110.19740.4957-0.2791-0.09510.0225-0.0675-0.036-0.07810.04-0.024122.6103-163.2777.8585
91.35630.054-0.08072.88581.19242.00520.0409-0.1672-0.02670.4313-0.10720.34710.3552-0.4720.0663-0.039-0.02280.0267-0.01160.0098-0.084921.1765-152.15518.7152
102.5502-0.0884-0.52812.16740.6582.88760.04040.00310.3005-0.2225-0.03270.0217-0.4973-0.1535-0.0077-0.02240.0540.0007-0.1369-0.0326-0.007130.7272-132.20511.1285
111.0528-0.19990.24971.59070.39361.04610.0307-0.14250.05720.2580.0539-0.12680.1144-0.1071-0.0846-0.0080.0103-0.0182-0.0528-0.0011-0.067331.524-148.46718.5571
121.93630.086-0.28851.17061.83973.70210.0212-0.0860.0285-0.08070.1015-0.4049-0.13270.2016-0.1227-0.0356-0.01850.0053-0.0729-0.01520.088745.4799-144.8167.2971
131.04390.07180.05661.83550.07181.98260.0373-0.0948-0.03580.19680.0267-0.28420.25520.0887-0.064-0.03530.0049-0.037-0.0894-0.0056-0.058934.2763-152.74314.6016
142.5391-1.2182-0.55321.0828-1.48323.7967-0.0964-0.1718-0.44810.326-0.0172-0.18580.48590.40760.11370.19530.1007-0.1204-0.20610.0658-0.006639.7951-171.07219.3463
153.5410.11830.7953.65220.9183.55950.03870.0130.4269-0.0318-0.04260.3702-0.5288-0.1660.00390.0182-0.00170.043-0.09770.0015-0.035541.2901-159.55858.3199
162.6573-0.31571.37141.5130.0412.22680.03240.2416-0.15910.13130.02680.03820.19050.1982-0.0592-0.0297-0.0085-0.0385-0.0533-0.0469-0.040946.1625-187.86251.89
173.6597-0.1637-0.43361.30960.07042.8280.0221-0.4255-0.10230.26370.06340.12350.0398-0.0266-0.08560.0611-0.031-0.0116-0.02820.0372-0.113346.0013-186.26869.1589
181.51550.08770.39751.36710.53881.19950.02730.15980.0392-0.09830.091-0.0804-0.09090.1662-0.1183-0.0296-0.04120.0155-0.0183-0.0079-0.110651.3786-173.23454.5382
194.11371.5539-1.22622.05090.06524.1001-0.02990.45040.4689-0.42350.1884-0.3647-0.44130.522-0.15840.0168-0.1640.1173-0.03550.0564-0.148960.0403-157.14646.0605
202.2271-0.619-0.75572.2529-1.16492.4780.07660.02730.39770.0966-0.1156-0.3718-0.49280.4640.039-0.0264-0.0798-0.0202-0.0840.02560.027961.6476-94.594413.5292
211.521-0.10340.31820.8765-0.17260.79530.0516-0.0198-0.0912-0.0239-0.0292-0.08810.05940.1106-0.0224-0.0470.0209-0.0121-0.0536-0.0058-0.046353.6615-113.28715.0471
221.4234-0.7445-0.49640.52951.01992.94580.1182-0.32890.2150.0416-0.0698-0.1122-0.2808-0.2403-0.0483-0.00140.0224-0.0295-0.0486-0.0507-0.030642.9923-93.728127.2539
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|9 - 102}
2X-RAY DIFFRACTION2{A|103 - 124}
3X-RAY DIFFRACTION3{A|125 - 144}
4X-RAY DIFFRACTION4{A|145 - 226}
5X-RAY DIFFRACTION5{A|227 - 252}
6X-RAY DIFFRACTION6{A|253 - 293}
7X-RAY DIFFRACTION7{A|294 - 354}
8X-RAY DIFFRACTION8{B|1 - 26}
9X-RAY DIFFRACTION9{B|27 - 70}
10X-RAY DIFFRACTION10{B|71 - 124}
11X-RAY DIFFRACTION11{B|125 - 226}
12X-RAY DIFFRACTION12{B|227 - 252}
13X-RAY DIFFRACTION13{B|253 - 317}
14X-RAY DIFFRACTION14{B|318 - 354}
15X-RAY DIFFRACTION15{C|7 - 53}
16X-RAY DIFFRACTION16{C|54 - 102}
17X-RAY DIFFRACTION17{C|103 - 124}
18X-RAY DIFFRACTION18{C|125 - 293}
19X-RAY DIFFRACTION19{C|294 - 355}
20X-RAY DIFFRACTION20{D|6 - 53}
21X-RAY DIFFRACTION21{D|54 - 293}
22X-RAY DIFFRACTION22{D|294 - 354}

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