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- PDB-6kgq: LSD1-FCPA-MPE five-membered ring adduct model -

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Basic information

Entry
Database: PDB / ID: 6kgq
TitleLSD1-FCPA-MPE five-membered ring adduct model
ComponentsLysine-specific histone demethylase 1A
KeywordsOXIDOREDUCTASE / DEMETHYLASE / AMINE OXIDASE / CHROMATIN / HISTONE / FAD / MECHANISM-BASED INHIBITOR
Function / homology
Function and homology information


guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylase activity / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / neuron maturation / muscle cell development / positive regulation of neural precursor cell proliferation ...guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylase activity / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / neuron maturation / muscle cell development / positive regulation of neural precursor cell proliferation / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / MRF binding / regulation of androgen receptor signaling pathway / DNA repair complex / nuclear androgen receptor binding / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of double-strand break repair via homologous recombination / positive regulation of neuroblast proliferation / DNA repair-dependent chromatin remodeling / positive regulation of stem cell proliferation / histone H3K9 demethylase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / histone methyltransferase complex / histone demethylase activity / positive regulation of cell size / positive regulation of epithelial to mesenchymal transition / response to fungicide / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / epigenetic regulation of gene expression / cellular response to cAMP / positive regulation of protein ubiquitination / Regulation of PTEN gene transcription / HDACs deacetylate histones / promoter-specific chromatin binding / cellular response to gamma radiation / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / HDMs demethylate histones / positive regulation of neuron projection development / cerebral cortex development / protein modification process / p53 binding / cellular response to UV / transcription corepressor activity / flavin adenine dinucleotide binding / regulation of protein localization / positive regulation of cold-induced thermogenesis / Factors involved in megakaryocyte development and platelet production / transcription regulator complex / Estrogen-dependent gene expression / DNA-binding transcription factor binding / Potential therapeutics for SARS / RNA polymerase II-specific DNA-binding transcription factor binding / transcription coactivator activity / oxidoreductase activity / chromosome, telomeric region / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / enzyme binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / identical protein binding / nucleus
Similarity search - Function
Histone lysine-specific demethylase / ATP synthase, gamma subunit, helix hairpin domain / SWIRM domain / SWIRM domain / SWIRM domain profile. / : / Amine oxidase / Flavin containing amine oxidoreductase / Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain / Homeobox-like domain superfamily ...Histone lysine-specific demethylase / ATP synthase, gamma subunit, helix hairpin domain / SWIRM domain / SWIRM domain / SWIRM domain profile. / : / Amine oxidase / Flavin containing amine oxidoreductase / Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain / Homeobox-like domain superfamily / FAD/NAD(P)-binding domain superfamily / Helix Hairpins / Arc Repressor Mutant, subunit A / Winged helix-like DNA-binding domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-DJC / FLAVIN-ADENINE DINUCLEOTIDE / Lysine-specific histone demethylase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.32 Å
AuthorsNiwa, H. / Sato, S. / Handa, N. / Umehara, T.
CitationJournal: Chemmedchem / Year: 2020
Title: Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors.
Authors: Niwa, H. / Sato, S. / Handa, N. / Sengoku, T. / Umehara, T. / Yokoyama, S.
History
DepositionJul 12, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 25, 2020Provider: repository / Type: Initial release
Revision 1.1May 20, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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 histone demethylase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,5334
Polymers74,3331
Non-polymers1,2003
Water2,954164
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1780 Å2
ΔGint-20 kcal/mol
Surface area29980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)185.268, 185.268, 109.327
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Space group name HallP612(x,y,z+5/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+2/3
#8: -x,-y,z+1/2
#9: y,x,-z+1/3
#10: -y,-x,-z+5/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+1/6
Components on special symmetry positions
IDModelComponents
11A-1160-

HOH

21A-1161-

HOH

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Components

#1: Protein Lysine-specific histone demethylase 1A / BRAF35-HDAC complex protein BHC110 / Flavin-containing amine oxidase domain-containing protein 2


Mass: 74333.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: SF file contains Friedel pairs. / Source: (gene. exp.) Homo sapiens (human) / Gene: KDM1A, AOF2, KDM1, KIAA0601, LSD1 / Plasmid: PETDUET-1 / Production host: Escherichia coli (E. coli) / Strain (production host): ROSETTA2(DE3) / References: UniProt: O60341, Oxidoreductases
#2: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#3: Chemical ChemComp-DJC / 3-[4-[5-fluoranyl-2-(trifluoromethyl)phenyl]phenyl]propanal


Mass: 296.259 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C16H12F4O
#4: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C27H33N9O15P2 / Comment: FAD*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 164 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Nonpolymer details6KGQ and 6KGR use the same data but have ligand models with possible different configurations.

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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: 3.73 Å3/Da / Density % sol: 67.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1M HEPES (pH 7.5), 5% MPD, 3.5-4.0% PEG MME 2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Nov 27, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.32→48.04 Å / Num. obs: 48179 / % possible obs: 100 % / Redundancy: 18.4 % / Biso Wilson estimate: 48.35 Å2 / CC1/2: 0.999 / Rpim(I) all: 0.021 / Rrim(I) all: 0.091 / Rsym value: 0.098 / Net I/σ(I): 24.4
Reflection shellResolution: 2.32→2.4 Å / Redundancy: 18.2 % / Mean I/σ(I) obs: 3 / Num. unique obs: 4362 / CC1/2: 0.896 / Rpim(I) all: 0.315 / Rrim(I) all: 1.363 / Rsym value: 1.326 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.16_3549+SVNrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.32→34.88 Å / SU ML: 0.2468 / Cross valid method: FREE R-VALUE / σ(F): 0.32 / Phase error: 21.9717
RfactorNum. reflection% reflection
Rfree0.1969 4559 5.02 %
Rwork0.1682 --
obs0.1697 48129 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 65.97 Å2
Refinement stepCycle: LAST / Resolution: 2.32→34.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5094 0 82 164 5340
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00745289
X-RAY DIFFRACTIONf_angle_d0.8887188
X-RAY DIFFRACTIONf_chiral_restr0.0526807
X-RAY DIFFRACTIONf_plane_restr0.0058964
X-RAY DIFFRACTIONf_dihedral_angle_d13.05863204
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.32-2.350.32061460.2872878X-RAY DIFFRACTION99.87
2.35-2.370.28811650.26872884X-RAY DIFFRACTION99.93
2.37-2.40.29441670.24822843X-RAY DIFFRACTION100
2.4-2.430.26941440.23912876X-RAY DIFFRACTION100
2.43-2.470.23931420.2252881X-RAY DIFFRACTION99.97
2.47-2.50.25511680.21842886X-RAY DIFFRACTION99.93
2.5-2.530.26821430.21742892X-RAY DIFFRACTION99.97
2.53-2.570.26781150.21382887X-RAY DIFFRACTION99.93
2.57-2.610.20851590.22012857X-RAY DIFFRACTION99.97
2.61-2.660.24371880.21372879X-RAY DIFFRACTION99.84
2.66-2.70.24731270.19562858X-RAY DIFFRACTION100
2.7-2.750.2331380.20492879X-RAY DIFFRACTION99.93
2.75-2.80.27261060.20822957X-RAY DIFFRACTION100
2.8-2.860.21581450.19882866X-RAY DIFFRACTION100
2.86-2.920.2651450.20182880X-RAY DIFFRACTION100
2.92-2.990.21451490.20922908X-RAY DIFFRACTION100
2.99-3.070.24551460.20362857X-RAY DIFFRACTION100
3.07-3.150.26111570.19762872X-RAY DIFFRACTION100
3.15-3.240.21581920.18552837X-RAY DIFFRACTION100
3.24-3.350.24471370.18362891X-RAY DIFFRACTION100
3.35-3.460.24341450.17842889X-RAY DIFFRACTION100
3.46-3.60.19981640.16952852X-RAY DIFFRACTION100
3.6-3.770.18031510.1572913X-RAY DIFFRACTION100
3.77-3.970.15441540.14482853X-RAY DIFFRACTION100
3.97-4.210.18581760.13642868X-RAY DIFFRACTION100
4.21-4.540.14641840.13132838X-RAY DIFFRACTION100
4.54-4.990.16531600.1322875X-RAY DIFFRACTION100
4.99-5.710.14911830.14912842X-RAY DIFFRACTION100
5.71-7.190.19191450.16222885X-RAY DIFFRACTION100
7.19-34.880.14281180.1282902X-RAY DIFFRACTION99.37
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)
12.517645071171.636444193420.6461862976723.238278639910.2181458132170.983304253310.0464125982262-0.2380026023930.0887114860638-0.0607617574518-0.0461853418008-0.336010873394-0.1505694031620.161722179998-0.005534894581570.381149696022-0.01792419552570.03124214407590.419959528814-0.06522191742960.30205744148944.1286348036-38.366316781522.0944028676
20.901094664728-1.33214592672-1.26234772865.779552757776.005980420996.691377761340.04453597330520.246117592967-0.453216805973-0.09674332123640.0162838752633-0.0771162599410.4604143192030.294242596147-0.0389534311740.7539762475250.1016002490030.0327813691950.628254805337-0.1527570550230.69365553081435.4192059797-82.5640295325-30.6654581554
31.613722894050.2777440357750.1125064639592.818872569170.7485314625081.923710812070.0909205292743-0.1776586311330.065225508173-0.171279505543-0.06450152860270.0277973891208-0.0831680278633-0.165635112744-0.02885958811260.257296890009-0.001287202927630.005682258800540.347604829234-0.001489356488460.24333546453125.2021986193-47.075981556214.5435363293
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 172 through 371 )
2X-RAY DIFFRACTION2chain 'A' and (resid 372 through 513 )
3X-RAY DIFFRACTION3chain 'A' and (resid 514 through 832 )

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