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- PDB-7vqs: Crystal structure of LSD1 in complex with compound 4 -

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Basic information

Entry
Database: PDB / ID: 7vqs
TitleCrystal structure of LSD1 in complex with compound 4
ComponentsLysine-specific histone demethylase 1A
KeywordsOXIDOREDUCTASE / DEMETHYLASE / AMINE OXIDASE / CHROMATIN / HISTONE / FAD / MECHANISM-BASED INHIBITOR
Function / homology
Function and homology information


guanine metabolic process / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / telomeric repeat-containing RNA binding / demethylase activity / regulation of DNA methylation-dependent heterochromatin formation / histone H3K4 demethylase activity / muscle cell development / positive regulation of neural precursor cell proliferation ...guanine metabolic process / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / telomeric repeat-containing RNA binding / demethylase activity / regulation of DNA methylation-dependent heterochromatin formation / histone H3K4 demethylase activity / muscle cell development / positive regulation of neural precursor cell proliferation / neuron maturation / regulation of androgen receptor signaling pathway / MRF binding / DNA repair complex / DNA repair-dependent chromatin remodeling / nuclear androgen receptor binding / regulation of double-strand break repair via homologous recombination / positive regulation of neuroblast proliferation / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of stem cell proliferation / negative regulation of DNA binding / histone H3K9 demethylase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / positive regulation of cell size / histone demethylase activity / response to fungicide / cellular response to cAMP / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / nuclear receptor coactivator activity / negative regulation of protein binding / Regulation of PTEN gene transcription / positive regulation of protein ubiquitination / 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 / negative regulation of DNA-binding transcription factor activity / cerebral cortex development / positive regulation of neuron projection development / cellular response to UV / regulation of protein localization / p53 binding / flavin adenine dinucleotide binding / positive regulation of cold-induced thermogenesis / Factors involved in megakaryocyte development and platelet production / DNA-binding transcription factor binding / Estrogen-dependent gene expression / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / chromosome, telomeric region / transcription coactivator activity / oxidoreductase activity / negative regulation of DNA-templated transcription / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / negative regulation of transcription by RNA polymerase II / enzyme binding / 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
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-0 kcal/mol
Surface area30190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)186.245, 186.245, 106.553
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 / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-TLA / L(+)-TARTARIC ACID / 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 / 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: 3.59 Å3/Da / Density % sol: 65.72 %
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: SPring-8 / Beamline: BL26B2 / Wavelength: 1 Å
DetectorType: RAYONIX MX225-HS / Detector: CCD / Date: Feb 16, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.94→48 Å / Num. obs: 23702 / % possible obs: 100 % / Redundancy: 18.3 % / Biso Wilson estimate: 86.36 Å2 / CC1/2: 0.999 / Rpim(I) all: 0.035 / Rrim(I) all: 0.15 / Rsym value: 0.146 / Net I/σ(I): 17.3
Reflection shellResolution: 2.94→3.12 Å / Redundancy: 18.6 % / Mean I/σ(I) obs: 1.9 / Num. unique obs: 3765 / CC1/2: 0.745 / Rpim(I) all: 0.536 / Rrim(I) all: 2.336 / Rsym value: 2.273 / % possible all: 100

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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 Å / SU ML: 0.4476 / Cross valid method: FREE R-VALUE / σ(F): 0.31 / Phase error: 28.8347
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2561 1238 5.23 %
Rwork0.2126 22415 -
obs0.2148 23653 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 98.99 Å2
Refinement stepCycle: LAST / Resolution: 2.94→48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5073 0 108 0 5181
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01065289
X-RAY DIFFRACTIONf_angle_d1.42157173
X-RAY DIFFRACTIONf_chiral_restr0.0746800
X-RAY DIFFRACTIONf_plane_restr0.0102964
X-RAY DIFFRACTIONf_dihedral_angle_d15.67811995
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.94-3.060.3261220.33452456X-RAY DIFFRACTION99.77
3.06-3.20.34821460.2892418X-RAY DIFFRACTION99.88
3.2-3.360.30031290.26732452X-RAY DIFFRACTION99.92
3.37-3.580.33891350.26492471X-RAY DIFFRACTION99.89
3.58-3.850.28381340.23132435X-RAY DIFFRACTION99.84
3.85-4.240.2521400.20342475X-RAY DIFFRACTION99.96
4.24-4.850.22941570.18442483X-RAY DIFFRACTION100
4.85-6.110.23881530.20482515X-RAY DIFFRACTION100
6.11-480.22091220.18332710X-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)
12.50851889425-1.30925556254-0.1909556608532.436856290370.1302714780390.944149319809-0.01834917562270.306027030539-0.1402509983270.3553404860240.0735040127917-0.1384117539560.2230341195860.256527940437-0.06659964266740.901388383197-0.1961237257170.1831817119640.876329967967-0.3028904369510.70718267904244.739117352937.8033915101-21.8093017752
2-0.316438269243-0.289386719810.0156481738391.73325197343.266076802295.11987922826-0.120345226201-0.01579798993290.0593324385797-0.1602249235520.205587218364-0.31616800865-0.6469190561290.401441156418-0.01610706665471.26372829529-0.264522287030.1133716235571.01887536529-0.2991697956220.8894884850234.750435212674.138284213918.2303513436
31.64782944707-0.723680611790.01739731561461.869738210280.397453591382.433829707560.10736227271-0.0616426724838-0.1212609971670.200760323519-0.1107583135770.2369590617170.0274556633814-0.3022477437240.00616411730030.762647259227-0.2570932691870.2780085819530.76363660745-0.2237294269070.73156646108324.033939361844.6171091266-16.4772410516
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 - 647

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