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- PDB-6dq7: LINKED KDM5A JMJ DOMAIN BOUND TO THE POTENTIAL HYDROLYSIS PRODUCT... -

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Basic information

Entry
Database: PDB / ID: 6dq7
TitleLINKED KDM5A JMJ DOMAIN BOUND TO THE POTENTIAL HYDROLYSIS PRODUCT OF INHIBITOR N45 i.e. 3-((6-(4-(2-cyano-3-methylbut-2-enoyl)-1,4-diazepan-1-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid
ComponentsLinked KDM5A Jmj Domain
KeywordsOXIDOREDUCTASE/INHIBITOR / DEMETHYLASE INHIBITION / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


facultative heterochromatin formation / [histone H3]-trimethyl-L-lysine4 demethylase / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / regulation of DNA-binding transcription factor activity / enzyme inhibitor activity / histone demethylase activity / Chromatin modifications during the maternal to zygotic transition (MZT) / circadian regulation of gene expression / HDMs demethylate histones / chromatin DNA binding ...facultative heterochromatin formation / [histone H3]-trimethyl-L-lysine4 demethylase / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / regulation of DNA-binding transcription factor activity / enzyme inhibitor activity / histone demethylase activity / Chromatin modifications during the maternal to zygotic transition (MZT) / circadian regulation of gene expression / HDMs demethylate histones / chromatin DNA binding / histone binding / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / regulation of DNA-templated transcription / chromatin / nucleolus / positive regulation of DNA-templated transcription / 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-H6M / : / Lysine-specific demethylase 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.852 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: Structure-based Engineering of Reversible Covalent Inhibitors Against Histone Lysine Demethylase 5A
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)38,5545
Polymers37,9451
Non-polymers6104
Water3,639202
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area500 Å2
ΔGint-4 kcal/mol
Surface area13800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)117.506, 62.309, 46.695
Angle α, β, γ (deg.)90.00, 92.39, 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, 206 molecules

#2: Chemical ChemComp-H6M / N-{6-[4-(hydroxyacetyl)-1,4-diazepan-1-yl]-2-(pyridin-2-yl)pyrimidin-4-yl}-beta-alanine / hydrolysis product of 3-((6-(4-(2-cyano-3-methylbut-2-enoyl)-1,4-diazepan-1-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid


Mass: 400.432 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24N6O4 / 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 202 / Source method: isolated from a natural source / Formula: H2O

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Details

Nonpolymer detailsunexpectedly, we did not observe the terminal cyano-3-methylbut moiety of compound N45 (PDB ...unexpectedly, we did not observe the terminal cyano-3-methylbut moiety of compound N45 (PDB chemical component H6M) in the complex structure with KDM5A. It is unclear whether exposure to X-ray radiation influences the reactivity of the cyanoacrylate group or if other unknown chemical reactions could occur under the crystallization conditions. The inhibitor is modeled as if some hydrolysis has occurred.

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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: 2.25 Å3/Da / Density % sol: 45.35 %
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
PH range: 8.6-9.2

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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: Feb 13, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→33.14 Å / Num. obs: 28578 / % possible obs: 99.5 % / Redundancy: 5 % / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.037 / Net I/σ(I): 19.2
Reflection shellResolution: 1.85→1.92 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.593 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 2696 / CC1/2: 0.833 / Rpim(I) all: 0.299 / % possible all: 95.7

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Processing

Software
NameVersionClassification
PHENIX(dev_2666: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IVB

5ivb


Resolution: 1.852→33.14 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 22.32
RfactorNum. reflection% reflection
Rfree0.2093 1425 4.99 %
Rwork0.1918 --
obs0.1927 28572 99.31 %
Refinement stepCycle: LAST / Resolution: 1.852→33.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2322 0 40 202 2564
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d
X-RAY DIFFRACTIONf_angle_d0.4653375
X-RAY DIFFRACTIONf_dihedral_angle_d4.9011953
X-RAY DIFFRACTIONf_chiral_restr0.042345
X-RAY DIFFRACTIONf_plane_restr0.004442
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8521-1.91830.35581360.29682520X-RAY DIFFRACTION93
1.9183-1.99510.25281380.24342705X-RAY DIFFRACTION100
1.9951-2.08590.24171520.21192722X-RAY DIFFRACTION100
2.0859-2.19580.24041360.21162708X-RAY DIFFRACTION100
2.1958-2.33340.20751450.20522746X-RAY DIFFRACTION100
2.3334-2.51350.25851290.20542728X-RAY DIFFRACTION100
2.5135-2.76630.25081500.20622735X-RAY DIFFRACTION100
2.7663-3.16630.2131520.19142736X-RAY DIFFRACTION100
3.1663-3.98820.1981350.16692747X-RAY DIFFRACTION100
3.9882-33.14550.15791520.16772800X-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)
16.3153-0.87830.74563.50020.79742.5929-0.3575-0.0969-0.24640.18510.3196-0.3530.17790.32450.01950.27020.0138-0.01450.1869-0.00180.2261-19.09872.51539.0022
22.1121.1596-0.0933.32711.00731.68550.02490.024-0.23060.08150.0814-0.33280.13430.3065-0.09430.20530.0159-0.0270.22960.01650.2233-12.84986.75285.6953
32.40963.19470.32084.33590.49142.014-0.12180.42150.6471-0.01380.20760.3805-0.329-0.1368-0.02170.36450.05570.02480.2280.02460.295-30.68228.717512.1852
45.05743.0859-1.72636.032-2.09583.91740.1686-0.22770.22240.7148-0.0944-0.0429-0.61140.0439-0.10130.31350.0194-0.01530.2084-0.03910.2-25.341825.933423.6934
50.83550.680.96881.81460.56684.19840.1198-0.0991-0.08890.2632-0.0220.00870.5176-0.2149-0.05250.263-0.00060.05130.2315-0.00030.1844-32.955713.398921.749
61.9096-1.44470.2641.48260.04161.98620.05670.23050.8708-0.00850.0547-0.2302-0.37410.2052-0.08220.2971-0.07940.01950.2263-0.05410.3394-17.800225.57711.5191
72.3202-0.223-0.67343.5817-0.54131.78380.1583-0.07880.048-0.09530.0501-0.0045-0.09340.3255-0.22720.158-0.03710.0320.3119-0.0120.2642-5.28516.97691.8522
81.00930.39720.09761.15980.46681.31850.0010.02690.0561-0.02240.02040.0271-0.1517-0.0153-0.01450.16080.0043-0.01360.1260.01230.1499-23.061616.45126.5266
92.3236-3.1432-2.04996.68051.00685.40870.17930.7084-0.4627-0.6366-0.09580.70080.1866-0.8777-0.03730.2712-0.0558-0.04480.3450.00590.2953-37.83789.7219-5.1674
103.5793-0.8555-0.67384.52380.32786.216-0.3360.438-0.53470.2686-0.15250.16310.89230.03860.39890.36260.02410.04640.2813-0.05860.3177-38.831123.1529-4.2508
111.23320.29660.29011.89230.26372.3227-0.01750.0047-0.0184-00.03360.0720.0854-0.0796-0.0170.16010.0074-0.00330.14330.00960.157-26.459711.6965.7968
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 31 )
2X-RAY DIFFRACTION2chain 'A' and (resid 32 through 64 )
3X-RAY DIFFRACTION3chain 'A' and (resid 65 through 359 )
4X-RAY DIFFRACTION4chain 'A' and (resid 360 through 378 )
5X-RAY DIFFRACTION5chain 'A' and (resid 379 through 399 )
6X-RAY DIFFRACTION6chain 'A' and (resid 400 through 432 )
7X-RAY DIFFRACTION7chain 'A' and (resid 433 through 469 )
8X-RAY DIFFRACTION8chain 'A' and (resid 470 through 507 )
9X-RAY DIFFRACTION9chain 'A' and (resid 508 through 521 )
10X-RAY DIFFRACTION10chain 'A' and (resid 522 through 536 )
11X-RAY DIFFRACTION11chain 'A' and (resid 537 through 588 )

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