PDB-6zb3: N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH GSK620

ID or keywords:

Entry

Database: PDB / ID: 6zb3

Title

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH GSK620

Components

Bromodomain-containing protein 4

BRD4

Keywords

TRANSCRIPTION /

INHIBITOR /

HISTONE / EPIGENETIC READER /

BROMODOMAIN /

BRD4 / BROMODOMAIN CONTAINING PROTEIN 4 /

ANTAGONIST

Function / homology

Function and homology information

RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.419 Å

Authors

Chung, C.

Citation

Journal: J.Med.Chem. / Year: 2020
Title: The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.
Authors: Seal, J.T. / Atkinson, S.J. / Aylott, H. / Bamborough, P. / Chung, C.W. / Copley, R.C.B. / Gordon, L. / Grandi, P. / Gray, J.R.J. / Harrison, L.A. / Hayhow, T.G. / Lindon, M. / Messenger, C. ...

History

Deposition	Jun 6, 2020	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Aug 5, 2020	Provider: repository / Type: Initial release
Revision 1.1	Sep 23, 2020	Group: Database references / Category: citation / citation_author Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2	May 1, 2024	Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	6zb3.cif.gz	69.6 KB	Display	PDBx/mmCIF format
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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/zb/6zb3 ftp://data.pdbj.org/pub/pdb/validation_reports/zb/6zb3	HTTPS FTP

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Related structure data

Related structure data	6zb0C 6zb1C 6zb2C C: citing same article (ref.)
Similar structure data	6kef-d 6ft3-d 5wma-d 6yqz-d 4meo-d 6uvj-d 6fo5-d 5z8r-d 4cfk-d 5hq5-d 4cl9-d 5f62-d 5n16-3 5d3t-d 4mr4-d 5ad2-2 5i88-d 7khl-2 6g0f-d 6zf9-d 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	#7 - Jul 2000 Nucleosome similarity (1)

Deposited unit

AAA: Bromodomain-containing protein 4

hetero molecules

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

1

Idetical with deposited unit
defined by author
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	37.092, 44.337, 78.448
Angle α, β, γ (deg.)	90.000, 90.000, 90.000
Int Tables number	19
Space group name H-M	P2₁2₁2₁

#1: Protein	Bromodomain-containing protein 4 / BRD4 / Protein HUNK1 Mass: 15099.380 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical	ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂H₆O₂
#3: Chemical	ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400 / Polyethylene glycol Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₁₀H₂₂O₆ / Comment: precipitant*YM
#4: Chemical	ChemComp-QCZ / ~{N}5-cyclopropyl-~{N}3-methyl-2-oxidanylidene-1-(phenylmethyl)pyridine-3,5-dicarboxamide Mass: 325.362 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₁₈H₁₉N₃O₃ / Feature type: SUBJECT OF INVESTIGATION
#5: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 243 / Source method: isolated from a natural source / Formula: H₂O
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: 2.14 Å³/Da / Density % sol: 42.42 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion / Details: 30%w/v PEG3350, 0.1M NaAc, 0.1M MES, pH 6.5

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Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

ESRF

/ Beamline: ID23-1 / Wavelength: 0.9626 Å

Detector

Type: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 7, 2014

Radiation

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

Radiation wavelength

Wavelength: 0.9626 Å / Relative weight: 1

Reflection

Resolution: 1.419→78.448 Å / Num. all: 24339 / Num. obs: 24339 / % possible obs: 96.6 % / Redundancy: 5.9 % / R_pim(I) all: 0.026 / R_rim(I) all: 0.066 / R_sym value: 0.055 / Net I/av σ(I): 7 / Net I/σ(I): 21.4 / Num. measured all: 144211

Reflection shell

Diffraction-ID: 1

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Mean I/σ(I) obs	Num. measured all	Num. unique obs	R_pim(I) all	R_rim(I) all	R_sym value	Net I/σ(I) obs	% possible all
1.42-1.5	4	0.108	6.6	11379	2867	0.067	0.139	0.108	7.7	80.3
1.5-1.59	5.5	0.096	7.2	18341	3332	0.048	0.116	0.096	11.6	97.7
1.59-1.7	6.6	0.086	7.6	21258	3237	0.039	0.101	0.086	15.7	100
1.7-1.83	6.3	0.073	8.9	18901	2995	0.034	0.087	0.073	18.4	99.8
1.83-2.01	6.5	0.064	9.8	18255	2791	0.03	0.077	0.064	23.8	99.8
2.01-2.24	6.2	0.056	10.6	15780	2533	0.027	0.068	0.056	27.9	99.8
2.24-2.59	6.4	0.055	10.6	14343	2238	0.025	0.065	0.055	30.9	99.7
2.59-3.17	6.1	0.051	11.2	11842	1931	0.024	0.061	0.051	33.2	99.7
3.17-4.49	5.9	0.049	11.6	8917	1511	0.024	0.059	0.049	35.3	99.5
4.49-78.448	5.7	0.047	11.2	5195	904	0.022	0.056	0.047	34.4	99.6

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0258	refinement
XDS		data reduction
SCALA		data scaling

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: in house structure

Resolution: 1.419→38.599 Å / Cor.coef. F_o:F_c: 0.965 / Cor.coef. F_o:F_c free: 0.959 / SU B: 1.8 / SU ML: 0.037 / Cross valid method: FREE R-VALUE / ESU R: 0.067 / ESU R Free: 0.065
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.1816	1244	5.122 %
R_work	0.1631	23044	-
all	0.164	-	-
obs	-	24288	96.381 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL PLUS MASK

Displacement parameters

B_iso mean: 12.94 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	0.102 Å²	0 Å²	0 Å²
2-	-	0.13 Å²	-0 Å²
3-	-	-	-0.232 Å²

Refinement step

Cycle: LAST / Resolution: 1.419→38.599 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	1062	0	48	243	1353

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.004	0.013	1174
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.017	1082
X-RAY DIFFRACTION	r_angle_refined_deg	1.206	1.663	1592
X-RAY DIFFRACTION	r_angle_other_deg	1.264	1.598	2546
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	5.803	5	134
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	35.82	25.172	58
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	10.467	15	206
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	9.252	15	3
X-RAY DIFFRACTION	r_chiral_restr	0.062	0.2	148
X-RAY DIFFRACTION	r_gen_planes_refined	0.005	0.02	1260
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	217
X-RAY DIFFRACTION	r_nbd_refined	0.191	0.2	261
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.164	0.2	967
X-RAY DIFFRACTION	r_nbtor_refined	0.175	0.2	557
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.079	0.2	396
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.105	0.2	140
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.095	0.2	11
X-RAY DIFFRACTION	r_nbd_other	0.154	0.2	63
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.093	0.2	37
X-RAY DIFFRACTION	r_mcbond_it	0.683	1.298	524
X-RAY DIFFRACTION	r_mcbond_other	0.682	1.292	523
X-RAY DIFFRACTION	r_mcangle_it	1.205	2.903	656
X-RAY DIFFRACTION	r_mcangle_other	1.204	2.914	657
X-RAY DIFFRACTION	r_scbond_it	0.866	1.497	650
X-RAY DIFFRACTION	r_scbond_other	0.865	1.498	651
X-RAY DIFFRACTION	r_scangle_it	1.453	3.236	931
X-RAY DIFFRACTION	r_scangle_other	1.452	3.238	932
X-RAY DIFFRACTION	r_lrange_it	5.019	13.831	1448
X-RAY DIFFRACTION	r_lrange_other	5.018	13.839	1449

LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	R_factor all	Num. reflection all	Fsc free	Fsc work	% reflection obs (%)	WR_factor R_work
1.419-1.455	0.157	74	0.177	1247	0.176	1809	0.962	0.955	73.0238	0.158
1.455-1.495	0.214	77	0.172	1467	0.174	1809	0.948	0.954	85.351	0.154
1.495-1.539	0.161	89	0.177	1560	0.176	1736	0.956	0.953	94.9885	0.159
1.539-1.586	0.209	99	0.172	1577	0.174	1679	0.945	0.955	99.8213	0.157
1.586-1.638	0.218	76	0.167	1563	0.169	1639	0.941	0.961	100	0.154
1.638-1.695	0.172	82	0.168	1510	0.168	1593	0.963	0.96	99.9372	0.157
1.695-1.759	0.197	76	0.173	1446	0.175	1525	0.952	0.956	99.8033	0.166
1.759-1.831	0.204	93	0.168	1374	0.171	1474	0.95	0.96	99.5251	0.164
1.831-1.912	0.175	72	0.16	1354	0.161	1428	0.962	0.964	99.8599	0.16
1.912-2.005	0.168	62	0.161	1293	0.161	1362	0.967	0.966	99.486	0.165
2.005-2.113	0.216	69	0.158	1232	0.161	1305	0.955	0.97	99.6935	0.168
2.113-2.241	0.142	58	0.147	1167	0.146	1229	0.977	0.972	99.6745	0.159
2.241-2.395	0.167	58	0.161	1094	0.161	1155	0.97	0.967	99.7403	0.178
2.395-2.586	0.163	55	0.165	1030	0.165	1092	0.962	0.964	99.359	0.187
2.586-2.832	0.209	51	0.162	950	0.164	1010	0.947	0.962	99.1089	0.189
2.832-3.164	0.194	53	0.157	870	0.159	924	0.956	0.964	99.8918	0.184
3.164-3.649	0.149	31	0.154	779	0.154	815	0.975	0.97	99.3865	0.186
3.649-4.459	0.17	37	0.144	661	0.146	706	0.975	0.976	98.8669	0.187
4.459-6.265	0.18	19	0.184	543	0.184	564	0.961	0.964	99.6454	0.248
6.265-38.599	0.222	13	0.193	327	0.195	345	0.969	0.962	98.5507	0.267

Refinement TLS params.

Method: refined / Origin x: 25.3466 Å / Origin y: 40.931 Å / Origin z: 8.5972 Å

	11	12	13	21	22	23	31	32	33
T	0.0022 Å²	0.0018 Å²	0.0023 Å²	-	0.0017 Å²	0.0008 Å²	-	-	0.0237 Å²
L	0.0217 °²	0.0106 °²	-0.0768 °²	-	0.3101 °²	-0.0289 °²	-	-	0.3682 °²
S	-0.0038 Å °	-0.0034 Å °	0.0131 Å °	0.0061 Å °	0.0116 Å °	0.0016 Å °	0.0248 Å °	0.02 Å °	-0.0078 Å °

Refinement TLS group

Selection: ALL

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