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- PDB-2uxx: Human LSD1 Histone Demethylase-CoREST in complex with an FAD- tra... -

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Basic information

Entry
Database: PDB / ID: 2uxx
TitleHuman LSD1 Histone Demethylase-CoREST in complex with an FAD- tranylcypromine adduct
Components
  • LYSINE-SPECIFIC HISTONE DEMETHYLASE 1
  • REST COREPRESSOR 1
KeywordsOXIDOREDUCTASE/REPRESSOR / OXIDOREDUCTASE-REPRESSOR COMPLEX / HISTONE DEMETHYLASE / OXIDOREDUCTASE / NUCLEAR PROTEIN / PHOSPHORYLATION / TRANSCRIPTION REGULATION / TRANYLCYPROMINE / CHROMATIN REGULATOR / NUCLEOSOMES / TRANSCRIPTION / HOST-VIRUS INTERACTION / CHROMATIN DEMETHYLATION / FAD / LSD1 / COREST / REPRESSOR / DEPRESSION
Function / homology
Function and homology information


positive regulation of megakaryocyte differentiation / guanine metabolic process / : / 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 / : / 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 / nuclear androgen receptor binding / regulation of double-strand break repair via homologous recombination / DNA repair-dependent chromatin remodeling / 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 / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / cellular response to cAMP / 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 / cellular response to UV / p53 binding / flavin adenine dinucleotide binding / chromatin organization / regulation of protein localization / positive regulation of cold-induced thermogenesis / Factors involved in megakaryocyte development and platelet production / 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 / transcription coactivator activity / oxidoreductase activity / chromatin remodeling / negative regulation of gene expression / 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
Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1880 / : / Helical region in REST corepressor / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / ATP synthase, gamma subunit, helix hairpin domain ...Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1880 / : / Helical region in REST corepressor / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / ATP synthase, gamma subunit, helix hairpin domain / 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 / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / 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 / Up-down Bundle / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
FAD-trans-2-Phenylcyclopropylamine Adduct / Lysine-specific histone demethylase 1A / REST corepressor 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.74 Å
AuthorsYang, M. / Culhane, J.C. / Machius, M. / Cole, P.A. / Yu, H.
Citation
Journal: Biochemistry / Year: 2007
Title: Structural Basis for the Inhibition of the Lsd1 Histone Demethylase by the Antidepressant Trans-2-Phenylcyclopropylamine.
Authors: Yang, M. / Culhane, J.C. / Szewczuk, L.M. / Jalili, P. / Ball, H.L. / Machius, M. / Cole, P.A. / Yu, H.
#1: Journal: Molecular Cell / Year: 2006
Title: Structural Basis for Corest-Dependent Demethylation of Nucleosomes by the Human Lsd1 Histone Demethylase
Authors: Yang, M. / Gocke, C.B. / Luo, X. / Borek, D. / Tomchick, D.R. / Machius, M. / Otwinowski, Z. / Yu, H.
History
DepositionMar 30, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 21, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Mar 27, 2013Group: Atomic model / Derived calculations / Non-polymer description
Revision 1.3Jan 30, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.4Feb 6, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.5May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: LYSINE-SPECIFIC HISTONE DEMETHYLASE 1
B: REST COREPRESSOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,6926
Polymers100,5532
Non-polymers1,1394
Water1448
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6120 Å2
ΔGint-54.1 kcal/mol
Surface area46610 Å2
MethodPQS
Unit cell
Length a, b, c (Å)120.798, 178.500, 235.880
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein LYSINE-SPECIFIC HISTONE DEMETHYLASE 1 / FLAVIN-CONTAINING AMINE OXIDASE DOMAIN-CONTAINING PROTEIN 2 / BRAF35-HDAC COMPLEX PROTEIN BHC110 / ...FLAVIN-CONTAINING AMINE OXIDASE DOMAIN-CONTAINING PROTEIN 2 / BRAF35-HDAC COMPLEX PROTEIN BHC110 / LYSINE- SPECIFIC DEMETHYLASE 1


Mass: 74126.781 Da / Num. of mol.: 1
Fragment: SWIRM DOMAIN, AMINE OXIDASE DOMAIN AND LINKER, RESIDUES 171-836
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: MJ23 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / References: UniProt: O60341, Oxidoreductases
#2: Protein REST COREPRESSOR 1 / PROTEIN COREST / NUCLEAR RECEPTOR COREPRESSOR 2


Mass: 26425.729 Da / Num. of mol.: 1
Fragment: FRAGMENT OF SANT1, LINKER REGION AND SANT2 DOMAIN, RESIDUES 308-482
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: MJ65 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / References: UniProt: Q9UKL0

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Non-polymers , 4 types, 12 molecules

#3: Chemical ChemComp-FAJ / FAD-trans-2-Phenylcyclopropylamine Adduct / FAD-PCPA Adduct


Mass: 919.725 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H43N9O16P2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsTHE CONSTRUCT USED CONTAINS A LINKER ( MGSSHHHHHHSSGLVPRGSHMASMTGGQQMGRGSEFGR) FROM THE CLONING PROCEDURE.

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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: 6.2 Å3/Da / Density % sol: 80.3 % / Description: NONE
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: VAPOR DIFFUSION, SITTING DROP, 20 DEGREES. DROP: 0.8 MICRO-LITERS OF PROTEIN (10 MG/ML IN 25 MM HEPES, PH 7.4, 200 MM SODIUM CHLORIDE, 1 MM PMSF, 5 MM DTT) PLUS 0.8 MICRO-LITERS OF ...Details: VAPOR DIFFUSION, SITTING DROP, 20 DEGREES. DROP: 0.8 MICRO-LITERS OF PROTEIN (10 MG/ML IN 25 MM HEPES, PH 7.4, 200 MM SODIUM CHLORIDE, 1 MM PMSF, 5 MM DTT) PLUS 0.8 MICRO-LITERS OF CRYSTALLIZATION SOLUTION (0.8 M LITHIUM SULFATE, 0.8 M AMMONIUM SULFATE, 0.4 M SODIUM CHLORIDE, 0.1 M SODIUM CITRATE, PH 5.6, 10 MM DTT). RESERVOIR: 1 ML OF CRYSTALLIZATION SOLUTION. CRYSTALS APPEARED WITHIN 12 HOURS AND GREW TO THEIR FINAL SIZE WITHIN 10 DAYS. CRYO-PROTECTION SOLUTION: RESERVOIR SOLUTION PLUS 23 PERCENT (V/V) GLYCEROL.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97921
DetectorType: ADSC CCD / Detector: CCD / Date: Oct 18, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97921 Å / Relative weight: 1
ReflectionResolution: 2.75→49.2 Å / Num. obs: 65220 / % possible obs: 98 % / Observed criterion σ(I): -3 / Redundancy: 12.4 % / Biso Wilson estimate: 84.2 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 42
Reflection shellResolution: 2.75→2.78 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.62 / Mean I/σ(I) obs: 2 / % possible all: 80.9

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 2.74→49 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.924 / SU B: 20.293 / SU ML: 0.198 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.269 / ESU R Free: 0.23 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. RESIDUES 836 TO 852 IN LSD1 AS WELL AS RESIDUES 286 TO 307 AND RESIDUES 442 TO 482 IN COREST ARE DISORDERED.
RfactorNum. reflection% reflectionSelection details
Rfree0.26 1529 2.3 %RANDOM
Rwork0.235 ---
obs0.236 63643 97.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 99.6 Å2
Baniso -1Baniso -2Baniso -3
1-7.75 Å20 Å20 Å2
2---6.02 Å20 Å2
3----1.73 Å2
Refinement stepCycle: LAST / Resolution: 2.74→49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6295 0 76 8 6379
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0226505
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.071.9768824
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg1.4755797
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.2624.392296
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.591151131
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4151543
X-RAY DIFFRACTIONr_chiral_restr0.0680.2988
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025648
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1740.22829
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.2940.24508
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1140.2178
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1310.243
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1580.21
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.3411.54103
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.59926437
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.52632712
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.9034.52387
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.74→2.81 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.372 81
Rwork0.338 3754
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)
10.63640.7549-0.28952.1049-1.01651.1825-0.0473-0.27-0.26990.1248-0.2795-0.2132-0.02040.3070.3267-0.380.07430.1-0.24950.166-0.328860.505349.891333.9619
23.00954.1103-2.22236.8461-2.43211.9362-0.29470.26670.1716-0.63190.0774-0.41620.324-0.01650.2172-0.00020.00010.00020.00010.0001024.2047-1.722859.0045
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A171 - 835
2X-RAY DIFFRACTION2B309 - 440

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