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- PDB-7w3l: Crystal structure of LSD1 in complex with cis-4-Br-2,5-F2-PCPA (S1024) -

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Basic information

Entry
Database: PDB / ID: 7w3l
TitleCrystal structure of LSD1 in complex with cis-4-Br-2,5-F2-PCPA (S1024)
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 / histone H3K4 demethylase activity / telomeric repeat-containing RNA binding / 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 / histone H3K4 demethylase activity / telomeric repeat-containing RNA binding / 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 / Regulation of PTEN gene transcription / positive regulation of protein ubiquitination / HDACs deacetylate histones / promoter-specific chromatin binding / positive regulation of neuron projection development / cellular response to gamma radiation / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / HDMs demethylate histones / 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 / SWIRM domain / SWIRM domain / SWIRM domain profile. / : / Amine oxidase / Flavin containing amine oxidoreductase / Homeobox-like domain superfamily / FAD/NAD(P)-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
3-[4-bromanyl-2,5-bis(fluoranyl)phenyl]propanal / FLAVIN-ADENINE DINUCLEOTIDE / L(+)-TARTARIC ACID / Lysine-specific histone demethylase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsNiwa, H. / Sato, S. / Umehara, T.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)21K06461, 20H03388, 20K21406 Japan
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Structure-Activity Relationship and In Silico Evaluation of cis- and trans-PCPA-Derived Inhibitors of LSD1 and LSD2
Authors: Niwa, H. / Watanabe, C. / Sato, S. / Harada, T. / Watanabe, H. / Tabusa, R. / Fukasawa, S. / Shiobara, A. / Hashimoto, T. / Ohno, O. / Nakamura, K. / Tsuganezawa, K. / Tanaka, A. / Shirouzu, ...Authors: Niwa, H. / Watanabe, C. / Sato, S. / Harada, T. / Watanabe, H. / Tabusa, R. / Fukasawa, S. / Shiobara, A. / Hashimoto, T. / Ohno, O. / Nakamura, K. / Tsuganezawa, K. / Tanaka, A. / Shirouzu, M. / Honma, T. / Matsuno, K. / Umehara, T.
History
DepositionNov 25, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 14, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 21, 2022Group: Database references / Structure summary / Category: citation / struct
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _struct.title
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)76,07010
Polymers74,3331
Non-polymers1,7379
Water2,270126
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1710 Å2
ΔGint-7 kcal/mol
Surface area29900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)186.433, 186.433, 107.457
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
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

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Components

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Protein , 1 types, 1 molecules A

#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
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, [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase

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Non-polymers , 5 types, 135 molecules

#2: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#3: Chemical ChemComp-8A2 / 3-[4-bromanyl-2,5-bis(fluoranyl)phenyl]propanal


Mass: 249.052 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H7BrF2O
#4: Chemical ChemComp-TLA / L(+)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 126 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 3.63 Å3/Da / Density % sol: 66.08 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M MES (pH 6.6), 0.2M diammonium tartrate, 0.0005M TCEP, 10-12% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.919 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Mar 17, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.919 Å / Relative weight: 1
ReflectionResolution: 2.51→48.12 Å / Num. obs: 38005 / % possible obs: 99.9 % / Redundancy: 20 % / Biso Wilson estimate: 60.06 Å2 / Rsym value: 0.121 / Net I/σ(I): 20.4
Reflection shellResolution: 2.51→2.61 Å / Redundancy: 21 % / Mean I/σ(I) obs: 1.8 / Rsym value: 2.347 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874+SVNrefinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6KGP

6kgp


Resolution: 2.51→48.12 Å / SU ML: 0.346 / Cross valid method: FREE R-VALUE / σ(F): 0.47 / Phase error: 27.207
Stereochemistry target values: GEOSTD + MONOMER LIBRARY + CDL V1.2
RfactorNum. reflection% reflection
Rfree0.216 1916 5.01 %
Rwork0.178 --
obs0.181 37973 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 74.15 Å2
Refinement stepCycle: LAST / Resolution: 2.51→48.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5066 0 112 126 5304
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0085282
X-RAY DIFFRACTIONf_angle_d0.9637158
X-RAY DIFFRACTIONf_dihedral_angle_d18.8291952
X-RAY DIFFRACTIONf_chiral_restr0.051798
X-RAY DIFFRACTIONf_plane_restr0.005915
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.51-2.540.43781170.3232641X-RAY DIFFRACTION100
2.54-2.580.34681290.31482602X-RAY DIFFRACTION99
2.58-2.610.30141580.2952582X-RAY DIFFRACTION100
2.61-2.650.41141440.29022609X-RAY DIFFRACTION100
2.65-2.70.29191260.27582610X-RAY DIFFRACTION100
2.7-2.740.25951110.26822640X-RAY DIFFRACTION100
2.74-2.790.33781090.25642633X-RAY DIFFRACTION100
2.79-2.840.29691360.25752597X-RAY DIFFRACTION100
2.84-2.890.35971190.2372625X-RAY DIFFRACTION100
2.89-2.950.2781310.23922596X-RAY DIFFRACTION100
2.95-3.010.24211240.22732616X-RAY DIFFRACTION100
3.02-3.090.32091320.22612619X-RAY DIFFRACTION100
3.09-3.160.25371730.22332605X-RAY DIFFRACTION100
3.16-3.250.25961600.20672542X-RAY DIFFRACTION100
3.25-3.340.30351330.20172644X-RAY DIFFRACTION100
3.34-3.450.28161290.20642590X-RAY DIFFRACTION100
3.45-3.570.23291370.18832619X-RAY DIFFRACTION100
3.57-3.720.20171540.17912597X-RAY DIFFRACTION100
3.72-3.890.22681290.1652611X-RAY DIFFRACTION100
3.89-4.090.20861500.14692592X-RAY DIFFRACTION100
4.09-4.350.16781680.14232587X-RAY DIFFRACTION100
4.35-4.680.17051470.12762610X-RAY DIFFRACTION100
4.68-5.150.14461690.13322581X-RAY DIFFRACTION100
5.15-5.90.21761490.16052583X-RAY DIFFRACTION100
5.9-7.430.19161350.16362623X-RAY DIFFRACTION100
7.43-48.120.1371080.14492643X-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)
12.6198-1.7251-0.39323.17560.26970.8515-0.01090.2333-0.02820.24250.0553-0.26560.12650.1549-0.0430.5328-0.09180.03530.5162-0.1150.39244.431538.2388-21.7447
20.74090.92030.79944.31585.45336.8798-0.1361-0.09310.2594-0.25260.3881-0.2776-0.80420.6463-0.220.8972-0.09580.02050.7668-0.16620.669335.548282.13529.5127
31.3726-0.5291-0.07031.84710.49882.16090.08160.0319-0.1230.2482-0.04840.16880.021-0.1733-0.03230.4074-0.1180.10610.4183-0.08070.401725.584747.4165-14.1077
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 512 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 513 THROUGH 832 )

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