PDB-7xw8: Crystal structure of Lysine Specific Demethylase 1 (LSD1) with TA...

ID or keywords:

Entry

Database: PDB / ID: 7xw8

Title

Crystal structure of Lysine Specific Demethylase 1 (LSD1) with TAK-418 distomer, FAD-adduct

Components

Lysine-specific histone demethylase 1A

Keywords

OXIDOREDUCTASE / Inhibitor / TAK-418 / distomer / FAD-adduct

Function / homology

Function and homology information

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 ...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 / 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 / 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 / regulation of protein localization / cellular response to UV / p53 binding / 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 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

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT /

molecular replacement / Resolution: 2.28 Å

Authors

Oki, H.

Funding support

1items

Citation

Journal: Eur.J.Med.Chem. / Year: 2022
Title: Design, synthesis, and structure-activity relationship of TAK-418 and its derivatives as a novel series of LSD1 inhibitors with lowered risk of hematological side effects.
Authors: Hattori, Y. / Matsumoto, S. / Morimoto, S. / Daini, M. / Toyofuku, M. / Matsuda, S. / Baba, R. / Murakami, K. / Iwatani, M. / Oki, H. / Iwasaki, S. / Matsumiya, K. / Tominari, Y. / Kimura, H. / Ito, M.

History

Deposition	May 26, 2022	Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0	Oct 12, 2022	Provider: repository / Type: Initial release
Revision 1.1	Nov 29, 2023	Group: Data collection / Refinement description Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	7xw8.cif.gz	155.5 KB	Display	PDBx/mmCIF format
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PDBx/mmJSON format	7xw8.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	7xw8_validation.pdf.gz	1 MB	Display	wwPDB validaton report
Full document	7xw8_full_validation.pdf.gz	1 MB	Display
Data in XML	7xw8_validation.xml.gz	25.9 KB	Display
Data in CIF	7xw8_validation.cif.gz	37.1 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/xw/7xw8 ftp://data.pdbj.org/pub/pdb/validation_reports/xw/7xw8	HTTPS FTP

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Related structure data

Related structure data	2z5uS 7e0g S: Starting model for refinement
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#231 - Mar 2019 Measles Virus Proteins similarity (2) #155 - Nov 2012 Vitamin D Receptor similarity (1) #122 - Feb 2010 Enhanceosome similarity (1) #98 - Feb 2008 Small Interfering RNA similarity (1) #241 - Jan 2020 Twenty Years of Molecules similarity (1)

Deposited unit

A: Lysine-specific histone demethylase 1A

hetero molecules

75 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author

Unit cell

Length a, b, c (Å)	184.727, 184.727, 108.937
Angle α, β, γ (deg.)	90.000, 90.000, 120.000
Int Tables number	178
Space group name H-M	P6₁22

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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 / ...BRAF35-HDAC complex protein BHC110 / Flavin-containing amine oxidase domain-containing protein 2 / [histone H3]-dimethyl-L-lysine(4) FAD-dependent demethylase 1A Mass: 73853.422 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, [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase

#1: Protein

Lysine-specific histone demethylase 1A / BRAF35-HDAC complex protein BHC110 / Flavin-containing amine oxidase domain-containing protein 2 / ...

Mass: 73853.422 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, [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase

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Non-polymers , 5 types, 207 molecules

#2: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₃H₈O₃
#3: Chemical	ChemComp-MG / MAGNESIUM ION Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical	ChemComp-FA8 / [[(2R,3S,4S)-5-[(4AS)-7,8-DIMETHYL-2,4-DIOXO-4A,5-DIHYDROBENZO[G]PTERIDIN-10-YL]-2,3,4-TRIHYDROXY-PENTOXY]-HYDROXY-PHOSPHORYL] [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL HYDROGEN PHOSPHATE Mass: 787.566 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₇H₃₅N₉O₁₅P₂ / Details: TAK-418 distomer, covalently bound on FAD / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical	ChemComp-I00 / ~{N}-(oxan-4-yl)-5-(3-oxidanylidenepropyl)thiophene-3-carboxamide / TAK-418 derivertive Mass: 267.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₁₃H₁₇NO₃S / Feature type: SUBJECT OF INVESTIGATION
#6: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 202 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 3.63 Å³/Da / Density % sol: 66.14 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 Details: 0.1 M imidazole-HCl (pH 6.5), 10% PEG 3350, 10% 2-methyl-2,4-pentanediol and 50 mM ammonium formate

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Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

ALS

/ Beamline: 5.0.2 / Wavelength: 0.97645 Å

Detector

Type: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 19, 2014

Radiation

Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray

Radiation wavelength

Wavelength: 0.97645 Å / Relative weight: 1

Reflection

Resolution: 2.28→50 Å / Num. obs: 50185 / % possible obs: 100 % / Redundancy: 21.4 % / R_merge(I) obs: 0.116 / R_pim(I) all: 0.028 / R_rim(I) all: 0.119 / Χ²: 1.026 / Net I/σ(I): 8.2 / Num. measured all: 1076060

Reflection shell

Diffraction-ID: 1

Resolution (Å)	Redundancy (%)	Num. unique obs	CC_1/2	R_pim(I) all	Χ²	% possible all	R_merge(I) obs	R_rim(I) all
2.28-2.32	20.3	2455	0.927	0.339	0.985	100
2.32-2.36	22.1	2470	0.936	0.234	0.978	100
2.36-2.41	22.2	2462	0.943	0.202	0.998	100	0.935	0.956
2.41-2.46	22.2	2452	0.966	0.173	0.986	100	0.798	0.816
2.46-2.51	22.2	2467	0.974	0.146	1.007	100	0.672	0.688
2.51-2.57	22.2	2486	0.979	0.127	1.003	100	0.584	0.598
2.57-2.63	22.2	2463	0.987	0.109	1.01	100	0.503	0.515
2.63-2.7	21.8	2486	0.981	0.114	1.403	100	0.519	0.532
2.7-2.78	22.2	2496	0.991	0.079	1.009	100	0.364	0.373
2.78-2.87	22.1	2474	0.994	0.062	1.003	100	0.285	0.291
2.87-2.98	22.1	2500	0.997	0.047	1.009	100	0.217	0.223
2.98-3.09	22.1	2483	0.997	0.039	1.004	100	0.18	0.184
3.09-3.24	22	2501	0.998	0.028	1.009	100	0.131	0.134
3.24-3.41	21.8	2518	0.999	0.024	0.998	100	0.11	0.113
3.41-3.62	21.2	2504	0.999	0.023	1.076	100	0.102	0.105
3.62-3.9	19.8	2526	0.998	0.023	1.08	100	0.1	0.103
3.9-4.29	20.6	2537	0.999	0.018	0.995	100	0.079	0.081
4.29-4.91	20	2557	0.999	0.016	0.999	100	0.07	0.071
4.91-6.19	20.1	2601	0.999	0.015	1	100	0.067	0.069
6.19-50	19.9	2747	1	0.008	0.97	99.6	0.036	0.037

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Phasing

Phasing

Method:

molecular replacement

Phasing MR

R rigid body: 0.464

	Highest resolution	Lowest resolution
Rotation	44.37 Å	2.51 Å

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Processing

Software

Name	Version	Classification
SCALEPACK		data scaling
MOLREP		phasing
REFMAC	5.8.0258	refinement
PDB_EXTRACT	3.27	data extraction
HKL-2000		data reduction

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 2Z5U

2z5u

Resolution: 2.28→44.409 Å / Cor.coef. F_o:F_c: 0.954 / Cor.coef. F_o:F_c free: 0.941 / SU B: 5.607 / SU ML: 0.134 / Cross valid method: FREE R-VALUE / ESU R: 0.206 / ESU R Free: 0.178

	R_factor	Num. reflection	% reflection
R_free	0.2299	2413	4.832 %
R_work	0.1981	47524	-
all	0.2	-	-
obs	-	49937	99.436 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 50.805 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	1.279 Å²	0.639 Å²	0 Å²
2-	-	1.279 Å²	0 Å²
3-	-	-	-4.149 Å²

Refinement step

Cycle: LAST / Resolution: 2.28→44.409 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	5012	0	79	202	5293

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.004	0.012	5199
X-RAY DIFFRACTION	r_angle_refined_deg	1.132	1.655	7058
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	5.798	5	636
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	33.168	22.682	261
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	16.817	15	890
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	17.992	15	31
X-RAY DIFFRACTION	r_chiral_restr	0.085	0.2	670
X-RAY DIFFRACTION	r_gen_planes_refined	0.005	0.02	3997
X-RAY DIFFRACTION	r_nbd_refined	0.198	0.2	2212
X-RAY DIFFRACTION	r_nbtor_refined	0.305	0.2	3578
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.13	0.2	211
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.15	0.2	36
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.146	0.2	8
X-RAY DIFFRACTION	r_mcbond_it	5.701	6.315	2553
X-RAY DIFFRACTION	r_mcangle_it	7.418	10.598	3186
X-RAY DIFFRACTION	r_scbond_it	7.732	7.095	2646
X-RAY DIFFRACTION	r_scangle_it	10.504	11.489	3872
X-RAY DIFFRACTION	r_lrange_it	11.991	65.162	7646

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
2.28-2.339	0.293	185	0.271	3395	X-RAY DIFFRACTION	98.8404
2.339-2.403	0.281	165	0.239	3408	X-RAY DIFFRACTION	100
2.403-2.473	0.303	165	0.241	3271	X-RAY DIFFRACTION	100
2.473-2.549	0.232	151	0.22	3228	X-RAY DIFFRACTION	99.9704
2.549-2.632	0.259	151	0.209	3098	X-RAY DIFFRACTION	100
2.632-2.724	0.345	170	0.253	2999	X-RAY DIFFRACTION	99.7168
2.724-2.827	0.246	163	0.2	2889	X-RAY DIFFRACTION	100
2.827-2.942	0.255	133	0.21	2824	X-RAY DIFFRACTION	99.9662
2.942-3.072	0.277	138	0.209	2690	X-RAY DIFFRACTION	100
3.072-3.221	0.239	123	0.202	2581	X-RAY DIFFRACTION	100
3.221-3.395	0.244	123	0.21	2454	X-RAY DIFFRACTION	99.4597
3.395-3.6	0.255	116	0.213	2300	X-RAY DIFFRACTION	98.5318
3.6-3.847	0.258	125	0.229	2091	X-RAY DIFFRACTION	95.5172
3.847-4.153	0.225	109	0.185	2010	X-RAY DIFFRACTION	98.1473
4.153-4.546	0.171	94	0.156	1916	X-RAY DIFFRACTION	99.9006
4.546-5.078	0.194	88	0.158	1740	X-RAY DIFFRACTION	99.9453
5.078-5.853	0.21	72	0.174	1557	X-RAY DIFFRACTION	100
5.853-7.144	0.233	68	0.21	1344	X-RAY DIFFRACTION	100
7.144-10.002	0.11	48	0.142	1064	X-RAY DIFFRACTION	100
10.002-44.409	0.128	26	0.18	665	X-RAY DIFFRACTION	98.433

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