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- PDB-5v9p: Crystal structure of pyrrolidine amide inhibitor [(3S)-3-(4-bromo... -

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Basic information

Entry
Database: PDB / ID: 5v9p
TitleCrystal structure of pyrrolidine amide inhibitor [(3S)-3-(4-bromo-1H-pyrazol-1-yl)pyrrolidin-1-yl][3-(propan-2-yl)-1H-pyrazol-5-yl]methanone (compound 35) in complex with KDM5A
Components(Lysine-specific demethylase ...) x 2
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / epigenetics / histone demethylase / cancer / inhibitor / selective / 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 / 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
Similarity search - Domain/homology
Chem-90S / NICKEL (II) ION / Lysine-specific demethylase 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsKiefer, J.R. / Liang, J. / Vinogradova, M.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors.
Authors: Liang, J. / Labadie, S. / Zhang, B. / Ortwine, D.F. / Patel, S. / Vinogradova, M. / Kiefer, J.R. / Mauer, T. / Gehling, V.S. / Harmange, J.C. / Cummings, R. / Lai, T. / Liao, J. / Zheng, X. ...Authors: Liang, J. / Labadie, S. / Zhang, B. / Ortwine, D.F. / Patel, S. / Vinogradova, M. / Kiefer, J.R. / Mauer, T. / Gehling, V.S. / Harmange, J.C. / Cummings, R. / Lai, T. / Liao, J. / Zheng, X. / Liu, Y. / Gustafson, A. / Van der Porten, E. / Mao, W. / Liederer, B.M. / Deshmukh, G. / An, L. / Ran, Y. / Classon, M. / Trojer, P. / Dragovich, P.S. / Murray, L.
History
DepositionMar 23, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 4, 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: Lysine-specific demethylase 5A
B: Lysine-specific demethylase 5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,2117
Polymers91,5732
Non-polymers6385
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area580 Å2
ΔGint-54 kcal/mol
Surface area27990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)158.949, 158.949, 90.594
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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Lysine-specific demethylase ... , 2 types, 2 molecules AB

#1: Protein Lysine-specific demethylase 5A / 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 / KDM5A


Mass: 90703.938 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM5A, JARID1A, RBBP2, RBP2 / Plasmid: pACGP67 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
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
#2: Protein/peptide Lysine-specific demethylase 5A / 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 / KDM5A


Mass: 869.063 Da / Num. of mol.: 1 / Fragment: Internal region with unknown reference frame
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM5A, JARID1A, RBBP2, RBP2 / Plasmid: pACGP67 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9

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Non-polymers , 5 types, 17 molecules

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


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-90S / [(3S)-3-(4-bromo-1H-pyrazol-1-yl)pyrrolidin-1-yl][3-(propan-2-yl)-1H-pyrazol-5-yl]methanone


Mass: 352.230 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H18BrN5O
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 3.64 Å3/Da / Density % sol: 66.23 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 7.3
Details: 200 uM inhibitor, 20% PEG3350, 0.1 M HEPES, pH 7.3, 12% glycerol

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Data collection

DiffractionMean temperature: 193 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Apr 9, 2014
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 3→35 Å / Num. obs: 26796 / % possible obs: 100 % / Redundancy: 8 % / Biso Wilson estimate: 51.91 Å2 / Rmerge(I) obs: 0.084 / Rpim(I) all: 0.031 / Rrim(I) all: 0.09 / Χ2: 0.9 / Net I/σ(I): 8.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
3-3.057.20.8120.6540.3240.8750.766100
3.05-3.117.40.6980.8080.2740.7510.791100
3.11-3.177.40.5920.8350.2320.6360.79499.9
3.17-3.237.50.50.9040.1940.5370.796100
3.23-3.37.60.4250.9290.1640.4560.82100
3.3-3.387.70.350.9510.1340.3750.856100
3.38-3.467.70.310.9650.1190.3320.906100
3.46-3.567.80.2360.9830.0890.2530.87100
3.56-3.6680.2080.9870.0770.2220.876100
3.66-3.788.20.1730.990.0630.1840.948100
3.78-3.918.10.1330.9930.0490.1420.866100
3.91-4.078.10.0960.9970.0350.1020.77999.9
4.07-4.268.30.0750.9980.0270.080.754100
4.26-4.488.50.0660.9980.0240.070.816100
4.48-4.768.40.0590.9980.0220.0630.80199.9
4.76-5.138.50.0680.9970.0250.0731.064100
5.13-5.648.50.0770.9960.0280.0821.426100
5.64-6.458.40.0790.9960.0280.0841.618100
6.45-8.118.40.0490.9980.0180.0520.962100
8.11-3580.0230.9990.0090.0250.3899.9

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5CEH

5ceh


Resolution: 3→34.163 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 26.13
RfactorNum. reflection% reflection
Rfree0.2483 1153 4.9 %
Rwork0.2157 --
obs0.2173 23523 87.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 221.02 Å2 / Biso mean: 61.5634 Å2 / Biso min: 10.5 Å2
Refinement stepCycle: final / Resolution: 3→34.163 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4590 0 93 12 4695
Biso mean--62.59 24.85 -
Num. residues----577
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084806
X-RAY DIFFRACTIONf_angle_d0.946538
X-RAY DIFFRACTIONf_chiral_restr0.047703
X-RAY DIFFRACTIONf_plane_restr0.006844
X-RAY DIFFRACTIONf_dihedral_angle_d17.2872856
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.9946-3.13080.3449680.29851721178954
3.1308-3.29570.35541070.27542108221567
3.2957-3.5020.29381350.25822594272982
3.502-3.77210.2841960.23553050324697
3.7721-4.15110.23711600.201331713331100
4.1511-4.75040.19541700.174431753345100
4.7504-5.97980.21131470.195732393386100
5.9798-34.16570.24431700.215233123482100
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)
11.43780.6995-0.10270.6888-0.47130.526-0.03590.2155-0.459-0.12130.008-0.20750.20930.0052-0.22610.3985-0.1631-0.12450.2111-0.08240.2517-50.645531.2528.1327
21.06-0.4294-0.1590.45250.15940.2883-0.006-0.1328-0.07150.22610.1480.1357-0.0542-0.06390.1730.1878-0.0840.18350.3762-0.08830.3945-57.181654.952130.0396
31.3654-0.1188-0.63161.0411-0.15830.5448-0.0322-0.4526-0.194-0.0527-0.185-0.74770.16580.4414-0.30190.2044-0.03920.1750.620.10490.5345-55.484667.342135.4393
41.34380.10390.14391.45770.20151.02560.1118-0.2571-0.01540.1031-0.00830.10880.1857-0.1131-0.11710.2289-0.0968-0.02770.25150.02130.153-51.11543.40320.2254
51.28760.3006-0.08891.3413-0.23011.03240.01570.35520.8567-0.1708-0.05590.2508-0.4006-0.0998-0.01370.4281-0.0426-0.0260.32270.15410.425-54.888360.40111.4117
60.77470.29710.08490.1206-0.05770.8698-0.1860.55770.1437-0.55910.32240.05690.0376-0.078-0.08481.146-0.0670.09350.79110.10960.6767-51.46254.7637-13.4606
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 12 through 62 )A12 - 62
2X-RAY DIFFRACTION2chain 'A' and (resid 63 through 100 )A63 - 100
3X-RAY DIFFRACTION3chain 'A' and (resid 101 through 173 )A101 - 173
4X-RAY DIFFRACTION4chain 'A' and (resid 174 through 565 )A174 - 565
5X-RAY DIFFRACTION5chain 'A' and (resid 566 through 699 )A566 - 699
6X-RAY DIFFRACTION6chain 'A' and (resid 700 through 785 )A700 - 785

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