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- PDB-6dqd: LINKED KDM5A JMJ DOMAIN BOUND TO THE INHIBITOR N53 i.e. 2-(5-([1,... -

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Basic information

Entry
Database: PDB / ID: 6dqd
TitleLINKED KDM5A JMJ DOMAIN BOUND TO THE INHIBITOR N53 i.e. 2-(5-([1,1'-biphenyl]-3-yl)-4-(1-(2-(piperidin-1-yl)ethoxy)ethyl)-1H-pyrazol-1-yl)isonicotinic acid
ComponentsLinked KDM5A Jmj Domain
KeywordsOXIDOREDUCTASE/INHIBITOR / DEMETHYLASE INHIBITION / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


[histone H3]-trimethyl-L-lysine4 demethylase / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / facultative heterochromatin formation / regulation of DNA-binding transcription factor activity / histone demethylase activity / enzyme inhibitor activity / Chromatin modifications during the maternal to zygotic transition (MZT) / circadian regulation of gene expression / protein-DNA complex / HDMs demethylate histones ...[histone H3]-trimethyl-L-lysine4 demethylase / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / facultative heterochromatin formation / regulation of DNA-binding transcription factor activity / histone demethylase activity / enzyme inhibitor activity / Chromatin modifications during the maternal to zygotic transition (MZT) / circadian regulation of gene expression / protein-DNA complex / HDMs demethylate histones / chromatin DNA binding / histone binding / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / nucleolus / negative regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
: / : / : / : / Lysine-specific demethylase-like domain / : / PLU-1-like protein / Lysine-specific demethylase 5, C-terminal helical domain / Zinc finger, C5HC2-type / C5HC2 zinc finger ...: / : / : / : / Lysine-specific demethylase-like domain / : / PLU-1-like protein / Lysine-specific demethylase 5, C-terminal helical domain / Zinc finger, C5HC2-type / C5HC2 zinc finger / ARID DNA-binding domain / ARID DNA-binding domain superfamily / ARID/BRIGHT DNA binding domain / ARID domain profile. / BRIGHT, ARID (A/T-rich interaction domain) domain / ARID/BRIGHT DNA binding domain / JmjN domain / jmjN domain / JmjN domain profile. / Small domain found in the jumonji family of transcription factors / Cupin / JmjC domain, hydroxylase / A domain family that is part of the cupin metalloenzyme superfamily. / JmjC domain / JmjC domain profile. / Zinc finger, PHD-type, conserved site / PHD-finger / Zinc finger PHD-type signature. / Zinc finger PHD-type 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-H67 / : / Lysine-specific demethylase 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.987 Å
AuthorsHorton, J.R. / Cheng, X.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM049245-23 United States
Citation
Journal: To Be Published
Title: To be determined
Authors: Horton, J.R. / Liu, X. / Woodcock, C.B. / Shanks, J. / Zhang, X. / Rai, G. / Mott, B. / Jansen, D.J. / Kales, S. / Henderson, M.J. / Pohida, K. / Fang, Y. / Hu, X. / Jadhav, A. / Maloney, D. ...Authors: Horton, J.R. / Liu, X. / Woodcock, C.B. / Shanks, J. / Zhang, X. / Rai, G. / Mott, B. / Jansen, D.J. / Kales, S. / Henderson, M.J. / Pohida, K. / Fang, Y. / Hu, X. / Jadhav, A. / Maloney, D. / Hall, M.D. / Simeonov, A. / Fu, H. / Vertino, P.M. / Cheng, X.
#1: Journal: Cell Chem Biol / Year: 2016
Title: Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.
Authors: Horton, J.R. / Liu, X. / Gale, M. / Wu, L. / Shanks, J.R. / Zhang, X. / Webber, P.J. / Bell, J.S. / Kales, S.C. / Mott, B.T. / Rai, G. / Jansen, D.J. / Henderson, M.J. / Urban, D.J. / Hall, ...Authors: Horton, J.R. / Liu, X. / Gale, M. / Wu, L. / Shanks, J.R. / Zhang, X. / Webber, P.J. / Bell, J.S. / Kales, S.C. / Mott, B.T. / Rai, G. / Jansen, D.J. / Henderson, M.J. / Urban, D.J. / Hall, M.D. / Simeonov, A. / Maloney, D.J. / Johns, M.A. / Fu, H. / Jadhav, A. / Vertino, P.M. / Yan, Q. / Cheng, X.
#2: Journal: J. Biol. Chem. / Year: 2016
Title: Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases.
Authors: Horton, J.R. / Engstrom, A. / Zoeller, E.L. / Liu, X. / Shanks, J.R. / Zhang, X. / Johns, M.A. / Vertino, P.M. / Fu, H. / Cheng, X.
#3: Journal: J. Med. Chem. / Year: 2018
Title: Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A.
Authors: Horton, J.R. / Liu, X. / Wu, L. / Zhang, K. / Shanks, J. / Zhang, X. / Rai, G. / Mott, B.T. / Jansen, D.J. / Kales, S.C. / Henderson, M.J. / Pohida, K. / Fang, Y. / Hu, X. / Jadhav, A. / ...Authors: Horton, J.R. / Liu, X. / Wu, L. / Zhang, K. / Shanks, J. / Zhang, X. / Rai, G. / Mott, B.T. / Jansen, D.J. / Kales, S.C. / Henderson, M.J. / Pohida, K. / Fang, Y. / Hu, X. / Jadhav, A. / Maloney, D.J. / Hall, M.D. / Simeonov, A. / Fu, H. / Vertino, P.M. / Yan, Q. / Cheng, X.
History
DepositionJun 10, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 12, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Linked KDM5A Jmj Domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8377
Polymers37,9451
Non-polymers8926
Water3,009167
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1000 Å2
ΔGint-2 kcal/mol
Surface area14780 Å2
2
A: Linked KDM5A Jmj Domain
hetero molecules

A: Linked KDM5A Jmj Domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,67414
Polymers75,8902
Non-polymers1,78412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area3190 Å2
ΔGint-16 kcal/mol
Surface area28380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)116.610, 61.899, 46.649
Angle α, β, γ (deg.)90.00, 92.17, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Linked KDM5A Jmj Domain / Histone demethylase JARID1A / Jumonji/ARID domain-containing protein 1A / Retinoblastoma-binding ...Histone demethylase JARID1A / Jumonji/ARID domain-containing protein 1A / Retinoblastoma-binding protein 2 / RBBP-2


Mass: 37944.836 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM5A, JARID1A, RBBP2, RBP2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): GOLD C-PLUS
References: UniProt: P29375, 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, 173 molecules

#2: Chemical ChemComp-H67 / 2-[5-([1,1'-biphenyl]-3-yl)-4-{(1S)-1-[2-(piperidin-1-yl)ethoxy]ethyl}-1H-pyrazol-1-yl]pyridine-4-carboxylic acid


Mass: 496.600 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H32N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 167 / 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: 2.22 Å3/Da / Density % sol: 44.52 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop
Details: 1.2-1.35 M (NH4)2SO4, 0.1 M Tris-HCl (pH 8.6-9.2) 0-20% glycerol 25 mM (Na/K) dibasic/monobasic phosphate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Apr 24, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.987→30.95 Å / Num. obs: 22852 / % possible obs: 99.7 % / Redundancy: 4.9 % / Rmerge(I) obs: 0.161 / Rpim(I) all: 0.083 / Net I/σ(I): 9
Reflection shellResolution: 1.987→2.06 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.94 / Num. unique obs: 2231 / CC1/2: 0.492 / Rpim(I) all: 0.507 / % possible all: 97.7

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IVB

5ivb


Resolution: 1.987→30.95 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 22.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2174 1159 5.08 %
Rwork0.1887 --
obs0.1902 22831 99.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.987→30.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2377 0 58 168 2603
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032536
X-RAY DIFFRACTIONf_angle_d0.6283472
X-RAY DIFFRACTIONf_dihedral_angle_d4.1651964
X-RAY DIFFRACTIONf_chiral_restr0.043359
X-RAY DIFFRACTIONf_plane_restr0.005452
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9868-2.07720.27191230.27862573X-RAY DIFFRACTION94
2.0772-2.18670.23941500.24822675X-RAY DIFFRACTION100
2.1867-2.32370.24381370.22422739X-RAY DIFFRACTION100
2.3237-2.5030.27641480.21592713X-RAY DIFFRACTION100
2.503-2.75470.28291450.20252735X-RAY DIFFRACTION100
2.7547-3.1530.22161430.17972722X-RAY DIFFRACTION100
3.153-3.97120.16651470.15412727X-RAY DIFFRACTION100
3.9712-30.95320.19721660.16332788X-RAY DIFFRACTION100
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)
17.2158-0.37650.44042.64930.47171.85990.0980.1123-0.48860.15180.0012-0.45180.23190.3417-0.10390.2450.0269-0.0280.1388-0.00180.2671-17.39632.58548.4734
21.9461-0.2418-0.00222.70260.83041.79830.0380.00530.0368-0.01230.0604-0.2892-0.10670.1919-0.10120.1489-0.03290.00380.15540.06640.1203-17.76114.25698.0357
30.1233-0.23680.34630.4809-0.85722.01910.06520.2230.4777-0.20490.06190.447-0.3387-0.4855-0.10030.59120.0374-0.05080.3798-0.0340.5761-34.774434.989913.9551
42.33390.98910.30743.09740.20523.38960.0147-0.18080.06570.3474-0.03080.1881-0.0599-0.32860.02410.17030.01820.04530.1679-0.00810.1242-31.040718.735422.7306
53.0585-1.4717-0.37391.8781-0.20372.09150.17050.21111.04190.00270.0628-0.5973-0.43140.5381-0.19290.3228-0.12180.04590.2983-0.06490.3799-11.451426.50110.0631
61.43720.0010.01481.04740.28041.82110.03590.20520.0671-0.09110.0153-0.0897-0.0980.1951-0.04380.1386-0.00790.01790.11330.01970.1326-18.972216.31782.0872
71.0266-0.00310.53372.05590.212.2858-0.00520.08180.0318-0.14280.01550.1653-0.0531-0.1545-0.01130.1373-0.00270.01770.12460.01980.1444-28.765714.22363.719
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 12 through 31 )
2X-RAY DIFFRACTION2chain 'A' and (resid 32 through 81 )
3X-RAY DIFFRACTION3chain 'A' and (resid 82 through 362 )
4X-RAY DIFFRACTION4chain 'A' and (resid 363 through 405 )
5X-RAY DIFFRACTION5chain 'A' and (resid 406 through 432 )
6X-RAY DIFFRACTION6chain 'A' and (resid 433 through 521 )
7X-RAY DIFFRACTION7chain 'A' and (resid 522 through 588 )

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