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- PDB-6bgw: LINKED KDM5A JMJ DOMAIN BOUND TO THE INHIBITOR 2-((2-chlorophenyl... -

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Basic information

Entry
Database: PDB / ID: 6bgw
TitleLINKED KDM5A JMJ DOMAIN BOUND TO THE INHIBITOR 2-((2-chlorophenyl)(2-(4,4-difluoropiperidin-1-yl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid(Compound N41)
ComponentsLysine-specific demethylase 5A, linked KDM5A JMJ domain
KeywordsOXIDOREDUCTASE/INHIBITOR / DEMETHYLASE INHIBITION / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR COMPLEX / OXIDOREDUCTASE / 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-DKS / : / Lysine-specific demethylase 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.644 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: 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.
#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.
History
DepositionOct 29, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 28, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 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_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Lysine-specific demethylase 5A, linked KDM5A JMJ domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9889
Polymers37,9451
Non-polymers1,0438
Water3,657203
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1380 Å2
ΔGint-6 kcal/mol
Surface area15230 Å2
Unit cell
Length a, b, c (Å)116.577, 61.825, 46.758
Angle α, β, γ (deg.)90.00, 92.13, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-870-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Lysine-specific demethylase 5A, 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, 211 molecules

#2: Chemical ChemComp-DKS / 2-{(S)-(2-chlorophenyl)[2-(4,4-difluoropiperidin-1-yl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid


Mass: 449.878 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22ClF2N3O3 / 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.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 203 / 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: 44.56 %
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-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Nov 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.64→32.884 Å / Num. obs: 39550 / % possible obs: 98.6 % / Redundancy: 7.7 % / Rmerge(I) obs: 0.177 / Rpim(I) all: 0.066 / Net I/σ(I): 11.6
Reflection shellResolution: 1.64→1.69 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.814 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 2569 / CC1/2: 0.623 / Rpim(I) all: 0.427 / % possible all: 96.8

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Processing

Software
NameVersionClassification
PHENIXdev_2863refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5E6H

5e6h


Resolution: 1.644→32.884 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.35
RfactorNum. reflection% reflection
Rfree0.2131 1921 4.86 %
Rwork0.1884 --
obs0.1895 39550 97.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.644→32.884 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2443 0 66 203 2712
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022611
X-RAY DIFFRACTIONf_angle_d0.4913567
X-RAY DIFFRACTIONf_dihedral_angle_d9.6881510
X-RAY DIFFRACTIONf_chiral_restr0.046365
X-RAY DIFFRACTIONf_plane_restr0.004465
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6437-1.68480.3072990.27692319X-RAY DIFFRACTION83
1.6848-1.73030.2831400.24882647X-RAY DIFFRACTION97
1.7303-1.78120.24571480.24132665X-RAY DIFFRACTION98
1.7812-1.83870.24761190.22362698X-RAY DIFFRACTION98
1.8387-1.90440.22961440.21932685X-RAY DIFFRACTION98
1.9044-1.98070.23541340.20642689X-RAY DIFFRACTION98
1.9807-2.07080.22111400.19832699X-RAY DIFFRACTION99
2.0708-2.180.24571380.19352701X-RAY DIFFRACTION99
2.18-2.31650.22681510.18622700X-RAY DIFFRACTION99
2.3165-2.49530.21231410.19632755X-RAY DIFFRACTION99
2.4953-2.74630.20321480.19062737X-RAY DIFFRACTION99
2.7463-3.14350.18831350.18552749X-RAY DIFFRACTION100
3.1435-3.95930.21231460.16152751X-RAY DIFFRACTION100
3.9593-32.89030.18871380.17262834X-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)
12.45311.13950.83432.98810.99452.263-0.02250.215-0.27340.04620.1691-0.34670.04570.41-0.15740.19630.0087-0.01770.20.01010.2384-15.07574.60886.4655
25.1579-1.04490.35192.89010.09042.6251-0.318-0.04650.9379-0.08250.05530.4556-0.4731-0.36440.2380.33660.061-0.02420.21680.00020.3033-32.327730.748912.6741
32.75131.79910.57353.48160.64413.6227-0.0076-0.25660.08840.4069-0.08070.14560.0391-0.1850.07740.20850.03840.03710.1632-0.01410.1465-30.795119.913922.457
41.9361-0.96-0.43231.3830.60631.3230.04790.16350.2412-0.08410.0489-0.2707-0.24250.3713-0.07390.2082-0.08040.02830.28860.01020.2795-8.259421.85053.8564
51.6906-0.05270.31621.51880.46062.1035-0.00460.1224-0.0257-0.0359-0.02680.1095-0.0822-0.09870.02760.15120.00110.00990.12190.01350.1439-27.368714.80573.447
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 62 )
2X-RAY DIFFRACTION2chain 'A' and (resid 63 through 359 )
3X-RAY DIFFRACTION3chain 'A' and (resid 360 through 405 )
4X-RAY DIFFRACTION4chain 'A' and (resid 406 through 459 )
5X-RAY DIFFRACTION5chain 'A' and (resid 460 through 588 )

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