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- PDB-9fwg: LSD1/CoREST bound to bomedemstat -

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Basic information

Entry
Database: PDB / ID: 9fwg
TitleLSD1/CoREST bound to bomedemstat
Components
  • Lysine-specific histone demethylase 1A
  • REST corepressor 1
KeywordsOXIDOREDUCTASE / bomedemstat / epigenetics / histone demethylase
Function / homology
Function and homology information


positive regulation of megakaryocyte differentiation / guanine metabolic process / regulation of DNA methylation-dependent heterochromatin formation / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / muscle cell development ...positive regulation of megakaryocyte differentiation / guanine metabolic process / regulation of DNA methylation-dependent heterochromatin formation / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / muscle cell development / neuron maturation / positive regulation of neural precursor cell proliferation / 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 / histone deacetylase complex / positive regulation of cell size / histone demethylase activity / positive regulation of epithelial to mesenchymal transition / response to fungicide / cellular response to cAMP / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / transcription repressor complex / erythrocyte differentiation / 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 / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / HDMs demethylate histones / negative regulation of DNA-binding transcription factor activity / cellular response to gamma radiation / cerebral cortex development / positive regulation of neuron projection development / transcription corepressor activity / regulation of protein localization / cellular response to UV / p53 binding / chromatin organization / positive regulation of cold-induced thermogenesis / Factors involved in megakaryocyte development and platelet production / flavin adenine dinucleotide binding / DNA-binding transcription factor binding / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / transcription regulator complex / Potential therapeutics for SARS / chromosome, telomeric region / oxidoreductase activity / transcription coactivator activity / negative regulation of gene expression / negative regulation of DNA-templated transcription / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / 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
: / Helical region in REST corepressor / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / SWIRM domain / SWIRM domain / SWIRM domain profile. ...: / Helical region in REST corepressor / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / SWIRM domain / SWIRM domain / SWIRM domain profile. / SANT domain profile. / SANT domain / Amine oxidase / Flavin containing amine oxidoreductase / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Homeobox-like domain superfamily / FAD/NAD(P)-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
: / Lysine-specific histone demethylase 1A / REST corepressor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsSperanzini, V. / Mattevi, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Prostate / Year: 2024
Title: Characterization of structural, biochemical, pharmacokinetic, and pharmacodynamic properties of the LSD1 inhibitor bomedemstat in preclinical models.
Authors: Jasmine, S. / Mandl, A. / Krueger, T.E.G. / Dalrymple, S.L. / Antony, L. / Dias, J. / Celatka, C.A. / Tapper, A.E. / Kleppe, M. / Kanayama, M. / Jing, Y. / Speranzini, V. / Wang, Y.Z. / Luo, ...Authors: Jasmine, S. / Mandl, A. / Krueger, T.E.G. / Dalrymple, S.L. / Antony, L. / Dias, J. / Celatka, C.A. / Tapper, A.E. / Kleppe, M. / Kanayama, M. / Jing, Y. / Speranzini, V. / Wang, Y.Z. / Luo, J. / Trock, B.J. / Denmeade, S.R. / Carducci, M.A. / Mattevi, A. / Rienhoff, H.Y. / Isaacs, J.T. / Brennen, W.N.
History
DepositionJun 30, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 10, 2024Provider: repository / Type: Initial release

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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
B: REST corepressor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)147,3513
Polymers146,4132
Non-polymers9381
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5210 Å2
ΔGint-42 kcal/mol
Surface area37370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)119.660, 179.020, 234.550
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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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: 93011.453 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 / Production host: Escherichia coli (E. coli) / References: UniProt: O60341, Oxidoreductases
#2: Protein REST corepressor 1 / Protein CoREST


Mass: 53401.352 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RCOR1, KIAA0071, RCOR / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UKL0
#3: Chemical ChemComp-A1IG2 / Bomedemstat FAD adduct


Mass: 937.715 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H42FN9O16P2 / Feature type: SUBJECT OF INVESTIGATION
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: 4.29 Å3/Da / Density % sol: 71.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: 100 mM N-(2-Acetamido)iminodiacetic acid (ADA) pH 6.5, 1.2 M Na/K Tartrate. Crystals were soaked in a solution containing 1 mM bomedemstat for 2 hours at 20 degress

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 2, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.2→99.48 Å / Num. obs: 40961 / % possible obs: 98.1 % / Redundancy: 3.4 % / CC1/2: 0.975 / Rmerge(I) obs: 0.191 / Rpim(I) all: 0.12 / Rrim(I) all: 0.227 / Net I/σ(I): 5 / Num. measured all: 141117
Reflection shellResolution: 3.2→3.33 Å / % possible obs: 96.8 % / Redundancy: 3.2 % / Rmerge(I) obs: 0.944 / Num. measured all: 14486 / Num. unique obs: 4520 / CC1/2: 0.38 / Rpim(I) all: 0.607 / Rrim(I) all: 1.129 / Net I/σ(I) obs: 1.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.2→98 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.881 / SU B: 35.922 / SU ML: 0.255 / Cross valid method: THROUGHOUT / ESU R: 0.406 / ESU R Free: 0.293 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22669 802 2 %RANDOM
Rwork0.19054 ---
obs0.1913 40152 97.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 83.047 Å2
Baniso -1Baniso -2Baniso -3
1-3.75 Å2-0 Å20 Å2
2--0.36 Å20 Å2
3----4.1 Å2
Refinement stepCycle: 1 / Resolution: 3.2→98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6293 0 64 0 6357
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0196493
X-RAY DIFFRACTIONr_bond_other_d0.0020.026277
X-RAY DIFFRACTIONr_angle_refined_deg2.2461.9738810
X-RAY DIFFRACTIONr_angle_other_deg1.187314437
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.355797
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.99224.475295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.052151130
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9771542
X-RAY DIFFRACTIONr_chiral_restr0.1170.2988
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0217311
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021470
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.445.4133194
X-RAY DIFFRACTIONr_mcbond_other3.445.4123193
X-RAY DIFFRACTIONr_mcangle_it5.5068.123989
X-RAY DIFFRACTIONr_mcangle_other5.5068.1223990
X-RAY DIFFRACTIONr_scbond_it4.3145.9983299
X-RAY DIFFRACTIONr_scbond_other4.3145.9983299
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.058.7784822
X-RAY DIFFRACTIONr_long_range_B_refined10.7151.44128031
X-RAY DIFFRACTIONr_long_range_B_other10.7151.44228032
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.2→3.283 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.389 56 -
Rwork0.339 2843 -
obs--94.99 %
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)
10.334-0.05330.20630.17750.33541.0605-0.0530.0112-0.15960.0329-0.14590.21930.0304-0.32240.19890.3086-0.05480.080.1248-0.14940.4159-15.333456.5011100.2287
20.3199-0.7013-0.39961.57670.94310.6685-0.0494-0.0093-0.0650.02150.0270.07840.01010.03090.02240.33930.00490.20160.0565-0.15050.552122.627618.72161.3248
30.2515-0.11870.05280.650.36560.92-0.01420.09130.01050.0143-0.17580.0319-0.0371-0.06190.190.34370.0219-0.02290.071-0.04760.3475-3.684664.877785.6649
43.47322.8146-3.58196.3293-0.33045.3484-0.24140.06210.16480.00650.6937-0.35450.37890.2991-0.45230.2040.03560.09860.2-0.15220.359419.35436.149479.5055
50.311-0.5158-0.34734.36012.71662.4922-0.2441-0.127-0.1861-0.41530.24490.8517-0.36850.6492-0.00080.3970.00460.11170.3473-0.24140.556128.558621.8253.0273
60.34520.63340.66661.21091.29711.40.0596-0.18910.07070.1287-0.24930.16970.1392-0.21510.18970.1846-0.03330.12130.31630.03170.294732.6434-25.810950.7215
72.1078-1.85510.4913.0519-0.06751.1308-0.2616-0.4054-0.12310.5170.22280.3635-0.21560.07330.03880.4824-0.03880.21420.1416-0.02210.163346.8767-24.134759.1722
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A171 - 371
2X-RAY DIFFRACTION2A372 - 539
3X-RAY DIFFRACTION3A540 - 836
4X-RAY DIFFRACTION4B308 - 329
5X-RAY DIFFRACTION5B330 - 370
6X-RAY DIFFRACTION6B371 - 384
7X-RAY DIFFRACTION7B385 - 440

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