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- PDB-5ly2: JMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Macrocyclic PEPTIDE ... -

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Basic information

Entry
Database: PDB / ID: 5ly2
TitleJMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Macrocyclic PEPTIDE Inhibitor CP2_R6Kme3 (13-mer)
Components
  • CP2_R6Kme3
  • Lysine-specific demethylase 4A
KeywordsOXIDOREDUCTASE / JMJD2A / KDM4A / NON-HEME / IRON / 2-OXOGLUTARATE / DIOXYGENASE / OXYGENASE / DOUBLE-STRANDED BETA HELIX / DSBH / FACIAL TRIAD / DEMETHYLASE / HISTONE / JMJC DOMAIN / METAL BINDING PROTEIN / EPIGENETIC AND TRANSCRIPTION REGULATION / CHROMATIN REGULATOR / HYDROXYLATION
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 / 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 / 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
NICKEL (II) ION / N-OXALYLGLYCINE / Lysine-specific demethylase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.43 Å
AuthorsChowdhury, R. / Madden, S.K. / Hopkinson, R. / Schofield, C.J.
Citation
Journal: Nat Commun / Year: 2017
Title: Highly selective inhibition of histone demethylases by de novo macrocyclic peptides.
Authors: Kawamura, A. / Munzel, M. / Kojima, T. / Yapp, C. / Bhushan, B. / Goto, Y. / Tumber, A. / Katoh, T. / King, O.N. / Passioura, T. / Walport, L.J. / Hatch, S.B. / Madden, S. / Muller, S. / ...Authors: Kawamura, A. / Munzel, M. / Kojima, T. / Yapp, C. / Bhushan, B. / Goto, Y. / Tumber, A. / Katoh, T. / King, O.N. / Passioura, T. / Walport, L.J. / Hatch, S.B. / Madden, S. / Muller, S. / Brennan, P.E. / Chowdhury, R. / Hopkinson, R.J. / Suga, H. / Schofield, C.J.
#1: Journal: Nature / Year: 2007
Title: Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity.
Authors: Ng, S.S. / Kavanagh, K.L. / McDonough, M.A. / Butler, D. / Pilka, E.S. / Lienard, B.M. / Bray, J.E. / Savitsky, P. / Gileadi, O. / von Delft, F. / Rose, N.R. / Offer, J. / Scheinost, J.C. / ...Authors: Ng, S.S. / Kavanagh, K.L. / McDonough, M.A. / Butler, D. / Pilka, E.S. / Lienard, B.M. / Bray, J.E. / Savitsky, P. / Gileadi, O. / von Delft, F. / Rose, N.R. / Offer, J. / Scheinost, J.C. / Borowski, T. / Sundstrom, M. / Schofield, C.J. / Oppermann, U.
#2: Journal: ACS Chem. Biol. / Year: 2014
Title: Substrate- and cofactor-independent inhibition of histone demethylase KDM4C.
Authors: Leurs, U. / Lohse, B. / Rand, K.D. / Ming, S. / Riise, E.S. / Cole, P.A. / Kristensen, J.L. / Clausen, R.P.
History
DepositionSep 23, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 12, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 19, 2017Group: Database references
Revision 1.2Jun 12, 2019Group: Data collection / Structure summary
Category: audit_author / database_PDB_rev / database_PDB_rev_record
Item: _audit_author.name
Revision 1.3Jul 6, 2022Group: Database references / Derived calculations / Source and taxonomy
Category: database_2 / pdbx_entity_src_syn ...database_2 / pdbx_entity_src_syn / pdbx_struct_conn_angle / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entity_src_syn.ncbi_taxonomy_id / _pdbx_entity_src_syn.organism_scientific / _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.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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 / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id
Revision 1.4Jan 17, 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

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
E: CP2_R6Kme3
F: CP2_R6Kme3
G: CP2_R6Kme3
H: CP2_R6Kme3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)186,74030
Polymers185,0188
Non-polymers1,72222
Water9,062503
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15540 Å2
ΔGint-172 kcal/mol
Surface area57330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.306, 103.747, 142.367
Angle α, β, γ (deg.)90.00, 99.14, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Protein/peptide , 2 types, 8 molecules ABCDEFGH

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


Mass: 44326.273 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: FRAGMENT: CATALYTIC DOMAIN (1-359) / Source: (gene. exp.) Homo sapiens (human) / Gene: KDM4A, JHDM3A, JMJD2, JMJD2A, KIAA0677 / Plasmid: PNIC28-BSA4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): R3
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: Protein/peptide
CP2_R6Kme3


Mass: 1928.174 Da / Num. of mol.: 4 / Source method: obtained synthetically / Details: Chemically synthesized / Source: (synth.) synthetic construct (others)

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Non-polymers , 6 types, 525 molecules

#3: Chemical
ChemComp-NI / NICKEL (II) ION


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


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-OGA / N-OXALYLGLYCINE


Mass: 147.086 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H5NO5 / Comment: inhibitor*YM
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 503 / 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: 2.3 Å3/Da / Density % sol: 46.47 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 0.1 M bicine pH 9.0 and 10% w/v polyethylene glycol 6000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 20, 2014 / Details: MIRRORS
RadiationMonochromator: SI 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.43→48.665 Å / Num. obs: 62112 / % possible obs: 98.3 % / Redundancy: 4.4 % / Biso Wilson estimate: 40.2 Å2 / Rmerge(I) obs: 0.138 / Net I/σ(I): 9.4167
Reflection shellResolution: 2.43→2.47 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.646 / Mean I/σ(I) obs: 2 / % possible all: 95

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
HKL-2000706Edata reduction
HKL-2000706Edata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OX0

2ox0


Resolution: 2.43→48.67 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.245 3236 5.22 %RANDOM
Rwork0.219 ---
obs0.22 62047 98.3 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 35.8 Å2 / ksol: 0.31 e/Å3
Displacement parametersBiso mean: 43 Å2
Baniso -1Baniso -2Baniso -3
1--0.62 Å20 Å2-2.25 Å2
2---2.56 Å20 Å2
3---3.19 Å2
Refinement stepCycle: LAST / Resolution: 2.43→48.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11486 0 83 503 12072
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00512032
X-RAY DIFFRACTIONf_angle_d1.26116362
X-RAY DIFFRACTIONf_dihedral_angle_d15.4256916
X-RAY DIFFRACTIONf_chiral_restr0.2151676
X-RAY DIFFRACTIONf_plane_restr0.0062100
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.43-2.46630.36141380.29922425X-RAY DIFFRACTION95
2.4663-2.50480.35471240.29742363X-RAY DIFFRACTION91
2.5048-2.54590.31251340.29832472X-RAY DIFFRACTION94
2.5459-2.58980.3241180.27932577X-RAY DIFFRACTION99
2.5898-2.63690.33671250.27732627X-RAY DIFFRACTION99
2.6369-2.68760.29881610.27012520X-RAY DIFFRACTION100
2.6876-2.74240.28011470.26142565X-RAY DIFFRACTION99
2.7424-2.80210.31111650.27742572X-RAY DIFFRACTION100
2.8021-2.86720.29181390.26292548X-RAY DIFFRACTION99
2.8672-2.93890.27071180.25542622X-RAY DIFFRACTION100
2.9389-3.01840.27381570.24022562X-RAY DIFFRACTION100
3.0184-3.10720.2961550.23522582X-RAY DIFFRACTION100
3.1072-3.20750.22971130.22542620X-RAY DIFFRACTION100
3.2075-3.32210.27311230.22432614X-RAY DIFFRACTION100
3.3221-3.4550.26311290.23252623X-RAY DIFFRACTION100
3.455-3.61220.27981430.21532578X-RAY DIFFRACTION99
3.6122-3.80260.23571560.21072554X-RAY DIFFRACTION100
3.8026-4.04080.2271600.19012564X-RAY DIFFRACTION99
4.0408-4.35260.21031660.18432559X-RAY DIFFRACTION99
4.3526-4.79020.17841310.16872428X-RAY DIFFRACTION93
4.7902-5.48260.20631470.17322531X-RAY DIFFRACTION97
5.4826-6.90430.2231430.20982633X-RAY DIFFRACTION100
6.9043-48.67490.20081440.20852672X-RAY DIFFRACTION99

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