PDB-5bwz: Crystal structure of S39E HDAC8 in complex with Droxinostat

ID or keywords:

Entry

Database: PDB / ID: 5bwz

Title

Crystal structure of S39E HDAC8 in complex with Droxinostat

Components

Histone deacetylase 8

Keywords

Hydrolase/Hydrolase Inhibitor / arginase/deacetylase fold /

hydrolase /

histone deacetylase / enzyme inhibitor-complex / Hydrolase-Hydrolase Inhibitor complex

Function / homology

Function and homology information

histone decrotonylase activity /

histone deacetylase / protein lysine deacetylase activity /

regulation of telomere maintenance /

Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / mitotic sister chromatid cohesion /

histone deacetylase activity / nuclear chromosome / Notch-HLH transcription pathway /

histone deacetylase complex ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.59 Å

Authors

Decroos, C. / Christianson, D.W.

Funding support

United States, 1items

Citation

Journal: Biochemistry / Year: 2019
Title: Phosphorylation of Histone Deacetylase 8: Structural and Mechanistic Analysis of the Phosphomimetic S39E Mutant.
Authors: Welker Leng, K.R. / Castaneda, C.A. / Decroos, C. / Islam, B. / Haider, S.M. / Christianson, D.W. / Fierke, C.A.

History

Deposition	Jun 8, 2015	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Jun 8, 2016	Provider: repository / Type: Initial release
Revision 1.1	Sep 20, 2017	Group: Author supporting evidence / Derived calculations / Category: pdbx_audit_support / pdbx_struct_oper_list Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2	Dec 25, 2019	Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3	Apr 22, 2020	Group: Database references / Category: citation / citation_author Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.4	Sep 27, 2023	Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	5bwz.cif.gz	308.2 KB	Display	PDBx/mmCIF format
PDB format	pdb5bwz.ent.gz	249.8 KB	Display	PDB format
PDBx/mmJSON format	5bwz.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/bw/5bwz ftp://data.pdbj.org/pub/pdb/validation_reports/bw/5bwz	HTTPS FTP

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Related structure data

Related structure data	3ewfS S: Starting model for refinement
Similar structure data	5ths-2 4qa3-1 4rn0-1 4qri-d 4rn2-2 3ezp-2 4qa3-2 7jvu-2 6hsk-2 5tht-2 Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) 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	#122 - Feb 2010 Enhanceosome similarity (1) #205 - Jan 2017 Nuclear Pore Complex similarity (1) #241 - Jan 2020 Twenty Years of Molecules similarity (1)

Deposited unit

A: Histone deacetylase 8

B: Histone deacetylase 8

hetero molecules

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

1

A: Histone deacetylase 8

hetero molecules

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

2

B: Histone deacetylase 8

hetero molecules

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

Unit cell

Length a, b, c (Å)	53.379, 84.390, 94.639
Angle α, β, γ (deg.)	90.00, 99.37, 90.00
Int Tables number	4
Space group name H-M	P12₁1

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Protein , 1 types, 2 molecules AB

#1: Protein	Histone deacetylase 8 / / HD8 Mass: 43274.027 Da / Num. of mol.: 2 / Mutation: S39E Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC8, HDACL1, CDA07 / Plasmid: pHD2-Xa-His / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q9BY41, histone deacetylase

#1: Protein

Histone deacetylase 8 /

/ HD8

Mass: 43274.027 Da / Num. of mol.: 2 / Mutation: S39E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Homo sapiens (human) / Gene: HDAC8, HDACL1, CDA07 / Plasmid: pHD2-Xa-His / Production host:

Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q9BY41,

histone deacetylase

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Non-polymers , 5 types, 773 molecules

#2: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical	ChemComp-K / POTASSIUM ION Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K
#4: Chemical	ChemComp-XCH / Droxinostat / 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide Mass: 243.687 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₁H₁₄ClNO₃
#5: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₃H₈O₃
#6: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 764 / Source method: isolated from a natural source / Formula: H₂O

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Experiment

Experiment	Method: X-RAY DIFFRACTION

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Sample preparation

Crystal	Density Matthews: 2.43 Å³/Da / Density % sol: 49.38 %
Crystal grow	Temperature: 294 K / Method: vapor diffusion, sitting drop / pH: 7 Details: 0.1 M BisTris (pH 6.5), 6% (w/v) PEG 8000, 4 mM TCEP

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Data collection

Diffraction	Mean temperature: 100 K
Diffraction source	Source: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
Detector	Type: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 13, 2013
Radiation	Monochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1.075 Å / Relative weight: 1
Reflection	Resolution: 1.59→43 Å / Num. obs: 110604 / % possible obs: 100 % / Redundancy: 7.4 % / R_merge(I) obs: 0.08 / Net I/σ(I): 19.3
Reflection shell	Resolution: 1.59→1.65 Å / Redundancy: 7.1 % / R_merge(I) obs: 0.605 / Mean I/σ(I) obs: 4.7 / % possible all: 100

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Processing

Software

Name	Version	Classification
PHENIX	DEV_1833	refinement
HKL-2000		data reduction
HKL-2000		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 3EWF

3ewf

Resolution: 1.59→42.98 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 15.59 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.16	5539	5.01 %
R_work	0.142	-	-
obs	0.143	110566	99.6 %

Solvent computation

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

Refinement step

Cycle: LAST / Resolution: 1.59→42.98 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	5467	0	44	764	6275

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.01	5860
X-RAY DIFFRACTION	f_angle_d	1.25	8007
X-RAY DIFFRACTION	f_dihedral_angle_d	12.417	2126
X-RAY DIFFRACTION	f_chiral_restr	0.059	882
X-RAY DIFFRACTION	f_plane_restr	0.007	1032

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 (%)
1.5909-1.6089	0.2083	184	0.1845	3187	X-RAY DIFFRACTION	91
1.6089-1.6279	0.199	177	0.1704	3521	X-RAY DIFFRACTION	100
1.6279-1.6477	0.1979	181	0.1623	3443	X-RAY DIFFRACTION	100
1.6477-1.6686	0.1896	209	0.157	3537	X-RAY DIFFRACTION	100
1.6686-1.6905	0.1669	178	0.1458	3484	X-RAY DIFFRACTION	100
1.6905-1.7137	0.1788	182	0.1452	3482	X-RAY DIFFRACTION	100
1.7137-1.7382	0.1688	177	0.1423	3507	X-RAY DIFFRACTION	100
1.7382-1.7641	0.1811	174	0.1403	3519	X-RAY DIFFRACTION	100
1.7641-1.7917	0.1669	170	0.1352	3557	X-RAY DIFFRACTION	100
1.7917-1.8211	0.1711	189	0.1337	3425	X-RAY DIFFRACTION	100
1.8211-1.8525	0.1612	177	0.1378	3541	X-RAY DIFFRACTION	100
1.8525-1.8861	0.1732	153	0.1343	3530	X-RAY DIFFRACTION	100
1.8861-1.9224	0.1622	169	0.147	3532	X-RAY DIFFRACTION	100
1.9224-1.9617	0.1683	203	0.1455	3483	X-RAY DIFFRACTION	100
1.9617-2.0043	0.1783	178	0.1417	3506	X-RAY DIFFRACTION	100
2.0043-2.0509	0.1696	209	0.1448	3499	X-RAY DIFFRACTION	100
2.0509-2.1022	0.1573	185	0.1386	3486	X-RAY DIFFRACTION	100
2.1022-2.1591	0.1631	186	0.1419	3519	X-RAY DIFFRACTION	100
2.1591-2.2226	0.1818	184	0.1419	3513	X-RAY DIFFRACTION	100
2.2226-2.2943	0.1789	185	0.1443	3478	X-RAY DIFFRACTION	100
2.2943-2.3763	0.1492	199	0.1411	3517	X-RAY DIFFRACTION	100
2.3763-2.4715	0.1722	179	0.1405	3524	X-RAY DIFFRACTION	100
2.4715-2.5839	0.1629	195	0.1443	3490	X-RAY DIFFRACTION	100
2.5839-2.7201	0.163	194	0.1441	3517	X-RAY DIFFRACTION	100
2.7201-2.8905	0.1773	206	0.1462	3492	X-RAY DIFFRACTION	100
2.8905-3.1137	0.1668	184	0.1451	3540	X-RAY DIFFRACTION	100
3.1137-3.4269	0.1484	192	0.143	3520	X-RAY DIFFRACTION	100
3.4269-3.9225	0.1236	159	0.1348	3552	X-RAY DIFFRACTION	100
3.9225-4.9407	0.1379	192	0.1225	3570	X-RAY DIFFRACTION	100
4.9407-42.9932	0.164	189	0.1594	3556	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	2.4663	-0.4601	-0.1707	2.1656	-0.4998	2.7912	0.0388	0.2661	0.1805	-0.166	-0.0037	0.2138	-0.1228	-0.5825	-0.0143	0.1827	0.0099	-0.0337	0.2611	-0.004	0.2326	-31.9476	-8.3696	-24.5346
2	1.1144	0.1259	-0.6675	0.6967	0.2387	1.8076	-0.0241	0.0541	-0.0943	-0.0016	-0.0045	0.2213	0.0657	-0.34	0.0345	0.1457	-0.0022	-0.0192	0.2036	0.0061	0.2231	-32.3985	-8.6689	-18.0908
3	2.1783	-0.1224	-0.4109	0.7371	0.1442	2.0092	0.0374	-0.0416	0.1654	0.012	-0.0203	0.157	-0.2301	-0.281	-0.0329	0.1526	0.0149	-0.0004	0.2082	0.0102	0.1862	-30.0338	-2.45	-12.9999
4	1.5452	-0.049	0.0599	0.709	0.3205	0.9801	-0.013	-0.3234	-0.0969	0.1375	-0.0246	0.0608	0.0402	-0.0241	0.043	0.1553	0.0157	-0.0016	0.1709	0.0343	0.1478	-17.9751	-7.3259	-6.0253
5	1.2305	0.1172	0.0194	0.8235	0.208	1.28	-0.0192	-0.031	-0.1683	-0.0189	0.013	-0.1002	0.1044	0.1409	0.0051	0.1352	0.0228	0.0023	0.1125	0.0026	0.1616	-11.3215	-9.6283	-19.9124
6	3.735	1.1519	-2.8166	1.788	-1.0218	4.7261	0.0298	-0.4704	-0.2842	0.1561	-0.1232	-0.2608	0.0726	0.2836	0.0541	0.1959	0.0323	-0.0726	0.3583	0.0651	0.2661	0.0171	-8.38	-2.8971
7	3.4867	0.9697	0.0033	2.7829	-0.464	3.1307	0.0382	-0.1348	0.0271	0.1744	-0.0607	0.2822	-0.0543	-0.7412	0.0086	0.2315	0.0474	0.0437	0.3076	-0.0284	0.2347	-28.6421	29.864	-24.2812
8	0.9673	-0.1322	0.4385	0.9721	0.0985	1.9603	-0.0247	0.0565	0.088	-0.0059	0.0283	0.2361	-0.1618	-0.3992	0.0199	0.1637	0.03	0.022	0.2298	0.0247	0.2273	-27.9222	27.3708	-31.1387
9	1.696	-0.281	0.0922	1.084	0.1283	2.0743	-0.0078	0.055	-0.0953	-0.0418	0.0107	0.1937	0.0307	-0.3314	-0.0279	0.1596	0.0111	-0.0003	0.2493	0.0238	0.187	-24.2405	23.5874	-34.4022
10	1.3345	-0.1569	0.1229	1.2061	-0.4053	1.6133	-0.0085	0.2557	0.0173	-0.1185	-0.0323	-0.0863	-0.0059	0.0542	0.0128	0.1452	-0.0114	0.008	0.1824	0.0105	0.1445	-9.3168	23.4078	-39.498
11	1.0483	-0.232	0.0649	1.0938	-0.1741	1.7024	-0.0184	-0.0341	0.141	0.13	0.0196	-0.0968	-0.219	0.0958	0.0109	0.1462	-0.0229	-0.0141	0.1093	-0.0104	0.156	-8.5593	28.0061	-23.1862
12	1.0284	-0.3446	0.0105	1.2636	-0.0835	1.8827	-0.0935	-0.0012	0.0848	0.1488	0.035	-0.2317	0.1066	0.3506	-0.0015	0.141	-0.018	-0.0465	0.1696	-0.0271	0.2151	-1.6812	20.8586	-22.1204

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	CHAIN 'A' AND (RESID 14 THROUGH 36 )
2	X-RAY DIFFRACTION	2	CHAIN 'A' AND (RESID 37 THROUGH 84 )
3	X-RAY DIFFRACTION	3	CHAIN 'A' AND (RESID 85 THROUGH 156 )
4	X-RAY DIFFRACTION	4	CHAIN 'A' AND (RESID 157 THROUGH 212 )
5	X-RAY DIFFRACTION	5	CHAIN 'A' AND (RESID 213 THROUGH 358 )
6	X-RAY DIFFRACTION	6	CHAIN 'A' AND (RESID 359 THROUGH 378 )
7	X-RAY DIFFRACTION	7	CHAIN 'B' AND (RESID 14 THROUGH 36 )
8	X-RAY DIFFRACTION	8	CHAIN 'B' AND (RESID 37 THROUGH 84 )
9	X-RAY DIFFRACTION	9	CHAIN 'B' AND (RESID 85 THROUGH 156 )
10	X-RAY DIFFRACTION	10	CHAIN 'B' AND (RESID 157 THROUGH 225 )
11	X-RAY DIFFRACTION	11	CHAIN 'B' AND (RESID 226 THROUGH 336 )
12	X-RAY DIFFRACTION	12	CHAIN 'B' AND (RESID 337 THROUGH 377 )

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