PDB-7xe3: Crystal structure of LSD2 in complex with cis-4-Br-2,5-F2-PCPA (S1024)

ID or keywords:

Entry

Database: PDB / ID: 7xe3

Title

Crystal structure of LSD2 in complex with cis-4-Br-2,5-F2-PCPA (S1024)

Components

Lysine-specific histone demethylase 1B

Keywords

OXIDOREDUCTASE / DEMETHYLASE / AMINE OXIDASE / CHROMATIN / HISTONE / FAD / MECHANISM-BASED INHIBITOR

Function / homology

Function and homology information

epigenetic programing of female pronucleus / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / genomic imprinting / histone demethylase activity / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / FAD binding / transcription initiation-coupled chromatin remodeling / HDMs demethylate histones / UCH proteinases ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.82 Å

Authors

Niwa, H. / Sato, S. / Umehara, T.

Funding support

Japan, 1items

Citation

Journal: Acs Med.Chem.Lett. / Year: 2022
Title: Structure-Activity Relationship and In Silico Evaluation of cis- and trans-PCPA-Derived Inhibitors of LSD1 and LSD2
Authors: Niwa, H. / Watanabe, C. / Sato, S. / Harada, T. / Watanabe, H. / Tabusa, R. / Fukasawa, S. / Shiobara, A. / Hashimoto, T. / Ohno, O. / Nakamura, K. / Tsuganezawa, K. / Tanaka, A. / Shirouzu, ...

History

Deposition	Mar 29, 2022	Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0	Sep 14, 2022	Provider: repository / Type: Initial release
Revision 1.1	Sep 21, 2022	Group: Database references / Structure summary / Category: citation / struct Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _struct.title
Revision 1.2	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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Download

PDBx/mmCIF format	7xe3.cif.gz	612.1 KB	Display	PDBx/mmCIF format
PDB format	pdb7xe3.ent.gz	504.6 KB	Display	PDB format
PDBx/mmJSON format	7xe3.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	7xe3_validation.pdf.gz	1011.7 KB	Display	wwPDB validaton report
Full document	7xe3_full_validation.pdf.gz	1 MB	Display
Data in XML	7xe3_validation.xml.gz	53.6 KB	Display
Data in CIF	7xe3_validation.cif.gz	74.5 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/xe/7xe3 ftp://data.pdbj.org/pub/pdb/validation_reports/xe/7xe3	HTTPS FTP

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Related structure data

Related structure data	7w3lC 7xe1C 7xe2C 4fweS S: Starting model for refinement C: citing same article (ref.)
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	#7 - Jul 2000 Nucleosome similarity (2) #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) #129 - Sep 2010 Isocitrate Dehydrogenase similarity (1) #154 - Oct 2012 Citric Acid Cycle similarity (1) #191 - Nov 2015 Glutamate-gated Chloride Receptors similarity (1) #215 - Nov 2017 Aspartate Transcarbamoylase similarity (1) #258 - Jun 2021 Glucocorticoid Receptor and Dexamethasone similarity (1) #89 - May 2007 Aconitase and Iron Regulatory Protein 1 similarity (1)

PDB pages

PDBj /

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NCBI

Related items in Molecule of the Month

#7 - Jul 2000
Nucleosome
similarity (2)
#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)
#129 - Sep 2010
Isocitrate Dehydrogenase
similarity (1)
#154 - Oct 2012
Citric Acid Cycle
similarity (1)
#191 - Nov 2015
Glutamate-gated Chloride Receptors
similarity (1)
#215 - Nov 2017
Aspartate Transcarbamoylase
similarity (1)
#258 - Jun 2021
Glucocorticoid Receptor and Dexamethasone
similarity (1)
#89 - May 2007
Aconitase and Iron Regulatory Protein 1
similarity (1)

Deposited unit

A: Lysine-specific histone demethylase 1B

B: Lysine-specific histone demethylase 1B

hetero molecules

181 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Lysine-specific histone demethylase 1B

hetero molecules

defined by author
Evidence: gel filtration
90.7 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

B: Lysine-specific histone demethylase 1B

hetero molecules

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

Unit cell

Length a, b, c (Å)	143.372, 171.226, 201.918
Angle α, β, γ (deg.)	90.00, 90.00, 90.00
Int Tables number	23
Space group name H-M	I222
Symmetry operation	#1: x,y,z #2: x,-y,-z #3: -x,y,-z #4: -x,-y,z #5: x+1/2,y+1/2,z+1/2 #6: x+1/2,-y+1/2,-z+1/2 #7: -x+1/2,y+1/2,-z+1/2 #8: -x+1/2,-y+1/2,z+1/2

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Protein , 1 types, 2 molecules AB

#1: Protein	Lysine-specific histone demethylase 1B / Flavin-containing amine oxidase domain-containing protein 1 / Lysine-specific histone demethylase 2 Mass: 89014.586 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: KDM1B, AOF1, C6orf193, LSD2 / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: Q8NB78, [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase

#1: Protein

Lysine-specific histone demethylase 1B / Flavin-containing amine oxidase domain-containing protein 1 / Lysine-specific histone demethylase 2

Mass: 89014.586 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Homo sapiens (human) / Gene: KDM1B, AOF1, C6orf193, LSD2 / Production host:

Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8NB78, [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase

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Non-polymers , 7 types, 226 molecules

#2: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#3: Chemical	ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE Mass: 785.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₇H₃₃N₉O₁₅P₂ / Comment: FAD*YM
#4: Chemical	ChemComp-8A2 / 3-[4-bromanyl-2,5-bis(fluoranyl)phenyl]propanal Mass: 249.052 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₉H₇BrF₂O
#5: Chemical	ChemComp-FLC / CITRATE ANION Mass: 189.100 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₆H₅O₇
#6: Chemical	ChemComp-PG4 / TETRAETHYLENE GLYCOL Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₈H₁₈O₅ / Comment: precipitant*YM
#7: Chemical	ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂H₆O₂
#8: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 212 / 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: 3.48 Å³/Da / Density % sol: 64.66 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion, sitting drop / Details: 330mM Ammonium citrate, 26% PEG 3350

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.919 Å
Detector	Type: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Mar 16, 2019
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.919 Å / Relative weight: 1
Reflection	Resolution: 2.82→48.27 Å / Num. obs: 60041 / % possible obs: 100 % / Redundancy: 6.8 % / B_iso Wilson estimate: 59.05 Å² / R_sym value: 0.138 / Net I/σ(I): 11.9
Reflection shell	Resolution: 2.82→2.89 Å / Mean I/σ(I) obs: 1.6 / R_sym value: 1.224

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Processing

Software

Name	Version	Classification
PHENIX	1.19.2_4158+SVN	refinement
XDS		data reduction
Aimless		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 4FWE

4fwe

Resolution: 2.82→48.27 Å / SU ML: 0.37 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 23.855
Stereochemistry target values: GEOSTD + MONOMER LIBRARY + CDL V1.2

	R_factor	Num. reflection	% reflection
R_free	0.222	3004	5.03 %
R_work	0.177	-	-
obs	0.179	60026	99.9 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL

Displacement parameters

B_iso mean: 68.22 Å²

Refinement step

Cycle: LAST / Resolution: 2.82→48.27 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	11758	0	172	212	12142

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.007	12223
X-RAY DIFFRACTION	f_angle_d	0.849	16577
X-RAY DIFFRACTION	f_dihedral_angle_d	13.861	4552
X-RAY DIFFRACTION	f_chiral_restr	0.048	1782
X-RAY DIFFRACTION	f_plane_restr	0.008	2197

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 (%)
2.82-2.85	0.3929	210	0.3258	3645	X-RAY DIFFRACTION	100
2.85-2.89	0.3648	191	0.3225	3643	X-RAY DIFFRACTION	100
2.89-2.92	0.3479	219	0.2918	3617	X-RAY DIFFRACTION	100
2.92-2.96	0.3394	184	0.2916	3676	X-RAY DIFFRACTION	100
2.96-3	0.3324	215	0.2894	3651	X-RAY DIFFRACTION	100
3-3.04	0.272	226	0.2799	3636	X-RAY DIFFRACTION	100
3.04-3.08	0.3149	159	0.2593	3710	X-RAY DIFFRACTION	100
3.08-3.13	0.3368	175	0.2464	3664	X-RAY DIFFRACTION	100
3.13-3.18	0.2947	192	0.2391	3659	X-RAY DIFFRACTION	100
3.18-3.23	0.2676	201	0.2292	3664	X-RAY DIFFRACTION	100
3.23-3.28	0.2512	192	0.2241	3667	X-RAY DIFFRACTION	100
3.28-3.34	0.2444	188	0.2311	3693	X-RAY DIFFRACTION	100
3.34-3.41	0.3212	199	0.2281	3614	X-RAY DIFFRACTION	100
3.41-3.48	0.2776	212	0.1982	3629	X-RAY DIFFRACTION	100
3.48-3.55	0.2182	163	0.1902	3676	X-RAY DIFFRACTION	100
3.55-3.64	0.2065	216	0.1703	3648	X-RAY DIFFRACTION	100
3.64-3.73	0.1858	209	0.1643	3627	X-RAY DIFFRACTION	100
3.73-3.83	0.2166	214	0.1534	3655	X-RAY DIFFRACTION	100
3.83-3.94	0.1906	214	0.1531	3677	X-RAY DIFFRACTION	100
3.94-4.07	0.1919	150	0.1499	3731	X-RAY DIFFRACTION	100
4.07-4.21	0.1813	200	0.1399	3610	X-RAY DIFFRACTION	100
4.21-4.38	0.188	171	0.1321	3678	X-RAY DIFFRACTION	100
4.38-4.58	0.1623	200	0.1306	3675	X-RAY DIFFRACTION	100
4.58-4.82	0.1899	178	0.1296	3662	X-RAY DIFFRACTION	100
4.82-5.12	0.1734	204	0.1312	3637	X-RAY DIFFRACTION	100
5.12-5.52	0.1908	198	0.1452	3672	X-RAY DIFFRACTION	100
5.52-6.07	0.2167	167	0.1534	3690	X-RAY DIFFRACTION	100
6.07-6.95	0.1822	184	0.1721	3684	X-RAY DIFFRACTION	100
6.95-8.74	0.1702	209	0.1539	3654	X-RAY DIFFRACTION	100
8.75-48.27	0.2258	172	0.1661	3681	X-RAY DIFFRACTION	99

Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

ID	L11 (°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)
1	3.3665	-0.0236	0.2292	3.9597	0.2583	3.8594	-0.039	0.167	0.0309	0.0637	-0.0071	0.8837	0.1506	-0.5373	0.0613	0.3983	-0.072	0.0125	0.414	0.0993	0.6302	13.9967	49.6038	36.7679
2	4.4031	4.0452	0.7027	5.0762	1.453	0.6938	-0.0293	-0.0599	-0.3863	0.2414	0.1048	-0.2425	0.0752	-0.0139	-0.0725	0.4497	0.0492	0.0193	0.2984	0.0738	0.414	34.3139	67.4332	39.9381
3	1.9749	0.2313	-0.0628	3.2394	-0.0044	1.1316	-0.0053	0.2218	-0.2157	-0.2867	0.1244	-0.7186	0.0359	0.1502	-0.0917	0.3181	-0.0081	0.0796	0.3698	-0.087	0.3868	51.3206	94.0217	34.5731
4	3.2457	0.2662	-1.0341	2.5901	-0.5606	4.8882	0.1947	0.5639	0.297	-0.4117	0.112	0.549	-0.4075	-1.5212	-0.2931	0.8309	0.0771	-0.1133	0.9332	0.1704	0.4633	24.7512	53.8342	0.6975
5	5.1674	-2.7484	1.8644	5.8281	-1.3576	5.1789	0.053	0.0883	-0.2662	-0.3968	0.03	0.0505	0.3413	0.0466	-0.0829	0.5155	-0.1037	-0.0099	0.4022	-0.004	0.2534	40.9904	43.2072	16.0847
6	2.8244	-0.0043	0.0435	1.705	-0.6182	2.1026	-0.0047	-0.0259	-0.3912	-0.0902	-0.1123	-0.3589	0.1106	0.3037	0.1139	0.3043	0.0306	-0.0112	0.3966	-0.0103	0.6195	61.8952	30.1136	38.9775

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	CHAIN 'A' AND (RESID 46 THROUGH 233 )
2	X-RAY DIFFRACTION	2	CHAIN 'A' AND (RESID 234 THROUGH 404 )
3	X-RAY DIFFRACTION	3	CHAIN 'A' AND (RESID 405 THROUGH 822 )
4	X-RAY DIFFRACTION	4	CHAIN 'B' AND (RESID 49 THROUGH 214 )
5	X-RAY DIFFRACTION	5	CHAIN 'B' AND (RESID 215 THROUGH 377 )
6	X-RAY DIFFRACTION	6	CHAIN 'B' AND (RESID 378 THROUGH 822 )

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