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- PDB-6g5x: Crystal Structure of KDM4A with compound YP-02-145 -

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Basic information

Entry
Database: PDB / ID: 6g5x
TitleCrystal Structure of KDM4A with compound YP-02-145
ComponentsLysine-specific demethylase 4A
KeywordsOXIDOREDUCTASE / KDM4A / ligand binding / drug design / inhibitor design / cancer / epigenetics
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 / response to nutrient levels / negative regulation of autophagy / 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
CITRIC ACID / Chem-MY7 / NICKEL (II) ION / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsMalecki, P.H. / Carter, D.M. / Gohlke, U. / Specker, E. / Nazare, M. / Weiss, M.S. / Heinemann, U.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Enhanced Properties of a Benzimidazole Benzylpyrazole Lysine Demethylase Inhibitor: Mechanism-of-Action, Binding Site Analysis, and Activity in Cellular Models of Prostate Cancer.
Authors: Carter, D.M. / Specker, E. / Malecki, P.H. / Przygodda, J. / Dudaniec, K. / Weiss, M.S. / Heinemann, U. / Nazare, M. / Gohlke, U.
History
DepositionMar 30, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 10, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2022Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / database_2 / pdbx_struct_conn_angle / struct_conn
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _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.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_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.ptnr3_label_seq_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
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Lysine-specific demethylase 4A
B: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,15217
Polymers83,5352
Non-polymers1,61715
Water9,926551
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A: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,61010
Polymers41,7681
Non-polymers8429
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5427
Polymers41,7681
Non-polymers7756
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.137, 148.615, 56.910
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Lysine-specific demethylase 4A / JmjC domain-containing histone demethylation protein 3A / Jumonji domain-containing protein 2A


Mass: 41767.543 Da / Num. of mol.: 2 / Fragment: JMJD2A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM4A, JHDM3A, JMJD2, JMJD2A, KIAA0677 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
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 , 7 types, 566 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-NI / NICKEL (II) ION / Nickel


Mass: 58.693 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ni
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-CIT / CITRIC ACID / Citric acid


Mass: 192.124 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H8O7
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-MY7 / 2-(3-methyl-5-oxidanylidene-4-phenyl-4~{H}-pyrazol-1-yl)-3~{H}-benzimidazole-5-carboxylic acid


Mass: 334.329 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H14N4O3
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 551 / 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: 2.51 Å3/Da / Density % sol: 50.98 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 5.5 / Details: 100mM Citrate, 10mM NiCl2, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 4, 2015
RadiationMonochromator: DOUBLE CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.78→46.84 Å / Num. obs: 81224 / % possible obs: 99.7 % / Redundancy: 5.891 % / Biso Wilson estimate: 28.7 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.051 / Rrim(I) all: 0.056 / Χ2: 1.002 / Net I/σ(I): 21.54
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
1.78-1.895.910.961.9128170.6991.05398.8
1.89-2.025.8410.5313.38122560.8690.58399.9
2.02-2.186.0770.2796.57114060.9670.305100
2.18-2.395.7390.15311.04105050.9870.168100
2.39-2.676.1240.09517.6495600.9950.104100
2.67-3.085.8170.05129.484730.9980.057100
3.08-3.776.0730.02654.84722710.02999.9
3.77-5.315.6520.01874.39567910.0299.9
5.31-46.845.3670.01877.8330110.01999.1

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHENIXrefinement
PDB_EXTRACT3.24data extraction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3PDQ

3pdq


Resolution: 1.78→46.84 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 22.05
RfactorNum. reflection% reflection
Rfree0.2033 2100 2.59 %
Rwork0.1701 --
obs0.171 81213 99.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 154.31 Å2 / Biso mean: 39.5807 Å2 / Biso min: 16.32 Å2
Refinement stepCycle: final / Resolution: 1.78→46.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5712 0 92 566 6370
Biso mean--39 43.12 -
Num. residues----695
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7796-1.8210.32671340.29125061519597
1.821-1.86650.31371380.264251965334100
1.8665-1.9170.28291390.250852415380100
1.917-1.97340.29281390.231352145353100
1.9734-2.03710.26531390.216852655404100
2.0371-2.10990.22161380.200852115349100
2.1099-2.19440.26261400.188552485388100
2.1944-2.29420.20991390.179952535392100
2.2942-2.41520.22041390.177752395378100
2.4152-2.56650.20451410.170853035444100
2.5665-2.76460.21971390.173752535392100
2.7646-3.04280.20371410.172553085449100
3.0428-3.4830.20141420.160353435485100
3.483-4.38770.15441430.137654085551100
4.3877-46.85650.17781490.15085570571999
Refinement TLS params.Method: refined / Origin x: 34.1027 Å / Origin y: 37.8547 Å / Origin z: 18.3969 Å
111213212223313233
T0.1847 Å2-0.0098 Å20.0128 Å2-0.1989 Å20.053 Å2--0.1673 Å2
L0.5744 °20.1476 °20.0361 °2-1.0408 °20.6325 °2--0.7163 °2
S0.0388 Å °0.042 Å °0.0522 Å °-0.1379 Å °-0.0208 Å °0.0143 Å °-0.1158 Å °-0.0128 Å °-0.0098 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA3 - 353
2X-RAY DIFFRACTION1allB11 - 354
3X-RAY DIFFRACTION1allE1 - 881
4X-RAY DIFFRACTION1allF1
5X-RAY DIFFRACTION1allG1
6X-RAY DIFFRACTION1allC1 - 2
7X-RAY DIFFRACTION1allC3
8X-RAY DIFFRACTION1allD1
9X-RAY DIFFRACTION1allJ1 - 3
10X-RAY DIFFRACTION1allJ4
11X-RAY DIFFRACTION1allJ5
12X-RAY DIFFRACTION1allL1 - 3
13X-RAY DIFFRACTION1allH1
14X-RAY DIFFRACTION1allI1

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