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- PDB-5vmp: Crystal Structure of Human KDM4 with Small Molecule Inhibitor QC5714 -

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Basic information

Entry
Database: PDB / ID: 5vmp
TitleCrystal Structure of Human KDM4 with Small Molecule Inhibitor QC5714
ComponentsLysine-specific demethylase 4A
KeywordsOXIDOREDUCTASE/INHIBITOR / KDM4 / Inhibitor-complex / demethylase / epigenetics / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


[histone H3]-trimethyl-L-lysine36 demethylase / histone H3K36me2/H3K36me3 demethylase activity / 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 / histone demethylase activity / pericentric heterochromatin ...[histone H3]-trimethyl-L-lysine36 demethylase / histone H3K36me2/H3K36me3 demethylase activity / 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 / histone demethylase activity / pericentric heterochromatin / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / 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 / 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-9FJ / NICKEL (II) ION / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsHosfield, D.J.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models.
Authors: Chen, Y.K. / Bonaldi, T. / Cuomo, A. / Del Rosario, J.R. / Hosfield, D.J. / Kanouni, T. / Kao, S.C. / Lai, C. / Lobo, N.A. / Matuszkiewicz, J. / McGeehan, A. / O'Connell, S.M. / Shi, L. / ...Authors: Chen, Y.K. / Bonaldi, T. / Cuomo, A. / Del Rosario, J.R. / Hosfield, D.J. / Kanouni, T. / Kao, S.C. / Lai, C. / Lobo, N.A. / Matuszkiewicz, J. / McGeehan, A. / O'Connell, S.M. / Shi, L. / Stafford, J.A. / Stansfield, R.K. / Veal, J.M. / Weiss, M.S. / Yuen, N.Y. / Wallace, M.B.
History
DepositionApr 28, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 27, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: 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)173,64916
Polymers171,9034
Non-polymers1,74612
Water4,396244
1
A: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4124
Polymers42,9761
Non-polymers4363
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4124
Polymers42,9761
Non-polymers4363
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4124
Polymers42,9761
Non-polymers4363
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Lysine-specific demethylase 4A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4124
Polymers42,9761
Non-polymers4363
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.140, 101.429, 142.673
Angle α, β, γ (deg.)90.000, 99.850, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 42975.770 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 (E. coli)
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
#2: Chemical
ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ni
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-9FJ / 3-({[(1R)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid


Mass: 312.363 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H20N2O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 244 / 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: 2.57 Å3/Da / Density % sol: 52.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 22% PEG4K, 100mM HEPES pH 7.5

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 25, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.48→50 Å / Num. obs: 57177 / % possible obs: 99 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.127 / Χ2: 1.035 / Net I/σ(I): 5.7 / Num. measured all: 214006
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.48-2.573.70.66456951.044199.8
2.57-2.673.80.5357721.0151100
2.67-2.793.80.41357471.061100
2.79-2.943.80.31957351.0571100
2.94-3.123.80.21457421.0691100
3.12-3.373.80.15357871.0391100
3.37-3.73.60.11853811.026193.7
3.7-4.243.70.0956531.02197.7
4.24-5.343.70.07558091.012199.8
5.34-503.70.06758561.004199.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
HKL-2000data collection
PDB_EXTRACT3.22data extraction
HKL-3000data reduction
HKL-3000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3PDQ

3pdq


Resolution: 2.48→50 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.902 / WRfactor Rfree: 0.2598 / WRfactor Rwork: 0.1914 / FOM work R set: 0.7918 / SU B: 10.99 / SU ML: 0.239 / SU R Cruickshank DPI: 0.5994 / SU Rfree: 0.305 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.599 / ESU R Free: 0.305 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2599 2904 5.1 %RANDOM
Rwork0.1931 ---
obs0.1965 54229 98.68 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 121.86 Å2 / Biso mean: 41.597 Å2 / Biso min: 13.69 Å2
Baniso -1Baniso -2Baniso -3
1--1.09 Å20 Å2-1.16 Å2
2--1.22 Å20 Å2
3---0.26 Å2
Refinement stepCycle: final / Resolution: 2.48→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11267 0 100 244 11611
Biso mean--30.36 34.14 -
Num. residues----1370
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.01911716
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210587
X-RAY DIFFRACTIONr_angle_refined_deg1.6351.95315857
X-RAY DIFFRACTIONr_angle_other_deg1.013324578
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.68551361
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.76523.157567
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.423151958
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.4831576
X-RAY DIFFRACTIONr_chiral_restr0.0950.21613
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02112890
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022630
LS refinement shellResolution: 2.481→2.545 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.348 194 -
Rwork0.261 3898 -
all-4092 -
obs--95.54 %

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