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- PDB-7vqu: Crystal structure of LSD1 in complex with compound S1427 -

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Basic information

Entry
Database: PDB / ID: 7vqu
TitleCrystal structure of LSD1 in complex with compound S1427
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 / 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
Chem-7UQ / 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: 2.94 Å
AuthorsNiwa, H. / Koda, Y. / Sato, S. / Yamamoto, H. / Koyama, H. / Umehara, T.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)20H03388, 20K21406 Japan
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles.
Authors: Koda, Y. / Sato, S. / Yamamoto, H. / Niwa, H. / Watanabe, H. / Watanabe, C. / Sato, T. / Nakamura, K. / Tanaka, A. / Shirouzu, M. / Honma, T. / Fukami, T. / Koyama, H. / Umehara, T.
History
DepositionOct 20, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 1, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 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)75,9328
Polymers74,3331
Non-polymers1,5997
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint-1 kcal/mol
Surface area30370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)188.248, 188.248, 106.997
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

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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
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
#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-TLA / L(+)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#4: Chemical ChemComp-7UQ / 3-[3,5-bis(fluoranyl)-2-[(2-fluoranylpyridin-3-yl)methoxy]phenyl]propanal


Mass: 295.256 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H12F3NO2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: FAD*YM
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: 3.68 Å3/Da / Density % sol: 66.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M MES (pH 6.2-6.3), 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: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Mar 16, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.94→48.45 Å / Num. obs: 24298 / % possible obs: 100 % / Redundancy: 19.8 % / Biso Wilson estimate: 90.41 Å2 / CC1/2: 1 / Rpim(I) all: 0.026 / Rrim(I) all: 0.116 / Rsym value: 0.113 / Net I/σ(I): 22.2
Reflection shellResolution: 2.94→3.12 Å / Mean I/σ(I) obs: 1.9 / Num. unique obs: 3843 / CC1/2: 0.834 / Rpim(I) all: 0.515 / Rrim(I) all: 2.358 / Rsym value: 2.3

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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: 2.94→48.45 Å / SU ML: 0.5013 / Cross valid method: FREE R-VALUE / σ(F): 0.13 / Phase error: 32.3525
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2576 1267 5.21 %
Rwork0.2192 42755 -
obs0.2212 24238 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 122.25 Å2
Refinement stepCycle: LAST / Resolution: 2.94→48.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5062 0 108 0 5170
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.015277
X-RAY DIFFRACTIONf_angle_d1.34037156
X-RAY DIFFRACTIONf_chiral_restr0.0727799
X-RAY DIFFRACTIONf_plane_restr0.0102961
X-RAY DIFFRACTIONf_dihedral_angle_d16.0211990
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.94-30.46481380.39462532X-RAY DIFFRACTION99.93
3-3.070.4064950.39212565X-RAY DIFFRACTION99.77
3.07-3.140.37211670.34292478X-RAY DIFFRACTION99.92
3.14-3.220.29861530.31782446X-RAY DIFFRACTION99.73
3.22-3.30.33531490.29692533X-RAY DIFFRACTION99.96
3.3-3.40.32051160.29592526X-RAY DIFFRACTION99.81
3.4-3.510.28981310.27822528X-RAY DIFFRACTION99.85
3.51-3.630.32581480.28022499X-RAY DIFFRACTION99.96
3.63-3.780.35791330.26182519X-RAY DIFFRACTION99.89
3.78-3.950.28421330.23542536X-RAY DIFFRACTION99.85
3.95-4.160.24861480.20782485X-RAY DIFFRACTION99.92
4.16-4.420.23451600.1862501X-RAY DIFFRACTION100
4.42-4.760.21061330.19042521X-RAY DIFFRACTION100
4.76-5.240.2251700.18652480X-RAY DIFFRACTION100
5.24-60.24281490.20612515X-RAY DIFFRACTION100
6-7.550.28061200.20932532X-RAY DIFFRACTION100
7.56-48.450.18371070.16542559X-RAY DIFFRACTION99.93
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)
12.84901458703-1.94528014776-0.7903694125683.322015783081.014780918361.84609114615-0.09146939279590.654689022203-0.3798675025880.693774098764-0.05550164828030.01243503765860.5656836188410.1514590352350.1407106106741.1487920151-0.3188287923280.2368740757791.08871241618-0.3887152648220.86534695386145.103838403537.9723010272-21.766096297
20.169443318206-0.190183737769-0.0209143126220.8885890678251.971734635983.76525572617-0.1751843378290.008549291964190.1235186686330.02650955329050.163610404387-0.218152967171-0.4496509730370.278974264650.09271674108011.49807853577-0.2426134205620.1293304151781.04769359894-0.2829235465560.98305268980835.25537562974.666907592218.2534894243
31.98065780798-0.9523749183810.1055501733832.554291749740.4316508902582.23856698234-0.09687752738860.523265790587-0.5616334353930.268705801078-0.1082238495370.4279620470470.239695622212-0.6083748876640.1515743632841.10764849307-0.3880584240110.465236322881.08719759705-0.4153068281761.0359748404324.378050104445.0758851498-16.4100488349
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 172 through 371 )172 - 3711 - 200
22chain 'A' and (resid 372 through 579 )372 - 579201 - 401
33chain 'A' and (resid 580 through 832 )580 - 832402 - 645

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