PDB-7mr5: Crystal structure of the first bromodomain (BD1) of human BRD4 bo...

ID or keywords:

Entry

Database: PDB / ID: 7mr5

Title

Crystal structure of the first bromodomain (BD1) of human BRD4 bound to GXH-II-052

Components

Bromodomain-containing protein 4

Keywords

GENE REGULATION / Bromosporine / BRD4 / BRD / BET

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: 1.82 Å

Authors

Chan, A. / Schonbrunn, E.

Funding support

United States, 1items

Citation

Journal: J.Med.Chem. / Year: 2022
Title: Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity.
Authors: Guan, X. / Cheryala, N. / Karim, R.M. / Chan, A. / Berndt, N. / Qi, J. / Georg, G.I. / Schonbrunn, E.

History

Deposition	May 7, 2021	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	May 18, 2022	Provider: repository / Type: Initial release
Revision 1.1	Aug 3, 2022	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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2	Aug 24, 2022	Group: Database references / Category: citation / citation_author Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3	Oct 18, 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	7mr5.cif.gz	132.3 KB	Display	PDBx/mmCIF format
PDB format	pdb7mr5.ent.gz	100.6 KB	Display	PDB format
PDBx/mmJSON format	7mr5.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	7mr5_validation.pdf.gz	855.1 KB	Display	wwPDB validaton report
Full document	7mr5_full_validation.pdf.gz	863.5 KB	Display
Data in XML	7mr5_validation.xml.gz	15.3 KB	Display
Data in CIF	7mr5_validation.cif.gz	20.7 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/mr/7mr5 ftp://data.pdbj.org/pub/pdb/validation_reports/mr/7mr5	HTTPS FTP

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Related structure data

Related structure data	7l9mC 7la9C 7mr6C 7mr7C 7mr9C 7mraC 7mrbC 7mrcC 7mrdC 7mrgC 7mrhC 8czaC 3mxfS 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

Deposited unit

A: Bromodomain-containing protein 4

B: Bromodomain-containing protein 4

hetero molecules

31.7 kDa, 2 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)	30.080, 39.710, 57.180
Angle α, β, γ (deg.)	99.950, 104.450, 89.990
Int Tables number	1
Space group name H-M	P1

#1: Protein	Bromodomain-containing protein 4 / Protein HUNK1 Mass: 15099.380 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: O60885
#2: Chemical	ChemComp-ZMS / N,N'-{oxybis[(ethane-2,1-diyl)oxy(1-oxoethane-2,1-diyl)piperidine-1,4-diyl]}bis{4-[(4-{4-chloro-3-[(2-methylpropane-2-sulfonyl)amino]anilino}-5-methylpyrimidin-2-yl)amino]-2-fluorobenzamide} Mass: 1366.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₆₂H₇₆Cl₂F₂N₁₄O₁₁S₂ / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂H₆O₂
#4: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 161 / 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: 2.16 Å³/Da / Density % sol: 42.92 %
Crystal grow	Temperature: 291 K / Method: vapor diffusion, hanging drop Details: 0.2 M Lithium sulfate monohydrate, 0.1 M TRIS hydrochloride pH 8.5, 30% w/v Polyethylene glycol 4 000

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Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

APS

/ Beamline: 22-ID / Wavelength: 1 Å

Detector

Type: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 10, 2018

Radiation

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

Radiation wavelength

Wavelength: 1 Å / Relative weight: 1

Reflection

Resolution: 1.82→29.368 Å / Num. obs: 20285 / % possible obs: 89.6 % / Redundancy: 3.688 % / B_iso Wilson estimate: 17.83 Å² / CC_1/2: 0.993 / R_merge(I) obs: 0.086 / R_rim(I) all: 0.1 / Χ²: 0.971 / Net I/σ(I): 10.97 / Num. measured all: 74812 / Scaling rejects: 157

Reflection shell

Diffraction-ID: 1

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Mean I/σ(I) obs	Num. unique obs	CC_1/2	R_rim(I) all	% possible all
1.82-1.87	3.632	0.291	5.56	1500	0.937	0.342	88.8
1.87-1.92	3.614	0.236	6.49	1428	0.952	0.277	87.6
1.92-1.97	3.565	0.2	7.22	1312	0.958	0.235	82.4
1.97-2.03	3.587	0.158	8.09	1258	0.973	0.186	82.3
2.03-2.1	3.751	0.155	8.69	1411	0.977	0.182	94.8
2.1-2.18	3.823	0.131	10.31	1389	0.978	0.153	95.1
2.18-2.26	3.832	0.119	10.89	1303	0.98	0.139	93.8
2.26-2.35	3.772	0.11	11.21	1288	0.983	0.129	94.1
2.35-2.45	3.774	0.105	11.65	1190	0.978	0.123	94.3
2.45-2.57	3.761	0.099	12.09	1136	0.982	0.116	92.3
2.57-2.71	3.721	0.095	12.49	1073	0.982	0.111	92
2.71-2.88	3.664	0.093	13.29	1020	0.981	0.109	92.3
2.88-3.08	3.629	0.085	13.78	932	0.986	0.1	89.3
3.08-3.32	3.555	0.077	14.4	853	0.987	0.09	86.6
3.32-3.64	3.488	0.071	14.9	680	0.989	0.084	78.7
3.64-4.07	3.67	0.068	15.85	669	0.989	0.079	82.1
4.07-4.7	3.722	0.065	16.16	659	0.99	0.077	93.5
4.7-5.76	3.727	0.071	16.17	542	0.989	0.083	89.4
5.76-8.14	3.735	0.067	16.15	423	0.992	0.079	90.6
8-29.368	3.521	0.058	15.89	219	0.992	0.068	88

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Processing

Software

Name	Version	Classification
XSCALE		data scaling
PHENIX	1.11.1-2575_2829	refinement
PDB_EXTRACT	3.27	data extraction
XDS		data reduction
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf

Resolution: 1.82→29.368 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 2.07 / Phase error: 21.32 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.2118	1197	5.9 %
R_work	0.1588	19084	-
obs	0.1618	20281	89.66 %

Solvent computation

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

Displacement parameters

B_iso max: 102.11 Å² / B_iso mean: 23.5246 Å² / B_iso min: 7.18 Å²

Refinement step

Cycle: final / Resolution: 1.82→29.368 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2124	0	101	161	2386
B_iso mean	-	-	27.55	29	-
Num. residues	-	-	-	-	254

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.007	2310
X-RAY DIFFRACTION	f_angle_d	1.045	3151
X-RAY DIFFRACTION	f_chiral_restr	0.047	321
X-RAY DIFFRACTION	f_plane_restr	0.006	401
X-RAY DIFFRACTION	f_dihedral_angle_d	12.442	1683

LS refinement shell

Refine-ID: X-RAY DIFFRACTION / R_factor R_free error: 0

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	% reflection obs (%)
1.82-1.8929	0.2566	134	0.1739	2134	89
1.8929-1.979	0.2051	122	0.165	1951	83
1.979-2.0833	0.2351	130	0.1623	2080	88
2.0833-2.2138	0.231	140	0.1584	2235	95
2.2138-2.3846	0.1993	140	0.1585	2229	94
2.3846-2.6245	0.2427	138	0.1726	2200	93
2.6245-3.0039	0.217	137	0.1715	2191	92
3.0039-3.7833	0.2154	121	0.1569	1925	81
3.7833-29.368	0.1779	135	0.1444	2139	91

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	6.9915	-5.8422	-4.4193	5.7409	3.4364	4.5674	-0.1413	-0.2416	0.0972	0.084	0.0987	0.0501	-0.079	0.1327	0.0318	0.0887	-0.0422	-0.0071	0.0955	-0.0104	0.1067	4.7744	24.1106	-36.9795
2	5.6756	3.1951	-0.6233	6.797	-0.0803	3.0112	-0.221	0.2761	-0.195	-0.4113	0.0142	-0.5156	-0.0479	-0.0054	0.1497	0.0699	-0.0334	0.0247	0.1697	-0.0077	0.1364	16.1095	20.3435	-48.1173
3	4.8251	-2.2995	-2.8682	2.4783	3.135	6.6522	0.2541	0.012	0.5214	-0.0875	0.0107	-0.2243	-0.3532	0.2188	-0.1062	0.1291	-0.0327	0.0202	0.0925	0.0137	0.1744	4.074	30.728	-45.645
4	1.5924	-0.3277	1.2349	3.6903	-0.0794	4.7386	-0.127	-1.4352	-0.4901	1.0908	0.5918	-0.0324	-0.5044	-1.0602	-0.4324	0.3831	0.0766	-0.0376	0.5464	0.0461	0.3194	-8.0342	39.9483	-30.7849
5	2.26	2.7759	-2.6025	6.4433	-2.9769	3.0876	0.1629	-0.0366	0.1291	-0.0701	0.0983	0.283	0.226	0.3272	0.0222	0.1608	0.0246	-0.0398	0.2044	-0.0189	0.2045	10.054	-0.7417	-73.6127
6	2.9279	-0.4377	-1.2308	9.6389	3.1999	7.935	0.0631	0.0711	-0.4031	0.1926	-0.3425	-0.1447	1.0904	0.2287	0.2531	0.2709	0.0525	0.0462	0.2395	0.0398	0.2268	20.9466	14.2215	-84.2126
7	2.087	-0.4268	-0.1968	1.4144	-0.3788	5.8601	0.1078	-0.0132	0.1761	0.0831	-0.1362	0.006	-0.7427	0.394	0.0037	0.1414	-0.016	0.0025	0.154	0.0112	0.1242	18.2766	20.1848	-67.452
8	1.7388	0.4558	0.553	1.3196	1.31	3.3622	0.2057	-0.1423	-0.395	0.3848	-0.0269	-0.2908	0.6265	-0.1405	0.0589	0.1948	-0.0136	-0.003	0.1324	0.0451	0.1744	6.388	4.4528	-60.4274
9	5.1376	1.4919	-2.4676	2.2677	-0.9668	2.4885	-0.1425	0.1461	0.014	-0.0055	0.0224	0.082	0.0896	0.0329	0.1355	0.096	0.0136	0.0022	0.1104	-0.0264	0.1216	8.7622	6.7207	-71.1758
10	3.3344	0.7123	-2.3198	4.3581	-2.8119	5.3816	0.0357	0.0862	-0.0978	-0.0818	-0.0668	-0.0305	-0.1329	0.4754	0.0855	0.1085	0.0052	0.0194	0.1577	0.0362	0.1084	17.5931	14.7972	-80.4166
11	6.8942	5.7848	-4.665	5.3612	-4.2169	5.3966	-0.0981	0.278	0.2357	-0.2209	0.1494	0.1347	0.1446	-0.0926	-0.0269	0.0956	0.0469	-0.0196	0.1187	-0.0036	0.1155	4.3847	14.1329	-71.1664
12	0.6993	-0.5475	-0.538	0.8015	-1.0997	6.2016	0.2194	-0.3445	0.1634	0.8701	-0.1798	1.1389	-0.337	-0.6326	0.2829	0.1816	0.0416	0.1185	0.2024	-0.0184	0.2991	-6.6205	10.2596	-59.6736
13	6.4636	4.3711	-3.7949	6.986	-3.0203	5.2742	0.0927	-0.1838	0.4515	-0.1084	-0.139	0.2297	-0.2269	0.066	-0.0955	0.1268	0.0099	-0.0097	0.0917	-0.0321	0.1252	5.2368	20.8371	-62.5802
14	7.4769	1.6538	1.07	8.5167	-1.2102	2.7818	0.0699	2.0864	0.5992	-1.2147	0.2881	-0.2819	-0.3843	0.3661	-0.0037	0.4748	-0.0017	-0.0206	0.4922	0.0577	0.3807	17.1907	29.807	-77.7584
15	7.75	-3.133	-1.8649	4.1441	3.6904	3.4884	-0.0088	0.1642	-0.286	0.1885	-0.0418	0.1969	0.4044	-0.3187	0.0467	0.1838	-0.028	-0.0033	0.1844	0.0494	0.1432	-1.7484	9.9603	-34.1893
16	3.0644	0.4859	-3.0997	2.2777	0.8288	4.8882	0.1955	-0.0803	-0.2845	0.2902	-0.6352	0.2571	0.8616	0.1207	0.4036	0.3002	-0.0724	0.0172	0.2295	-0.058	0.2077	-11.8264	24.0527	-24.0989
17	2.6029	-0.4645	0.6597	4.2301	0.3777	6.8032	0.0465	0.2097	0.1653	-0.1324	0.0315	0.1496	-0.4422	-0.5132	0.0879	0.1214	0.0381	-0.0219	0.1682	-0.033	0.1677	-11.3801	32.1328	-36.6992
18	4.6351	-2.2153	-1.1374	3.2048	2.4609	5.7794	0.1744	0.2725	0.2297	-0.1423	-0.2264	0.0838	-0.5865	-0.2912	-0.0387	0.1301	0.0076	-0.0012	0.0996	0.0163	0.135	-4.6726	26.7361	-48.0593
19	2.0988	-0.8732	1.3899	3.6751	-1.526	3.8473	0.0459	-0.0091	-0.2832	-0.172	-0.1253	0.031	0.346	0.1223	0.1089	0.1075	0.0019	0.0369	0.1287	0.0162	0.1559	4.918	11.8736	-42.4068
20	1.106	-1.7335	-0.906	3.8291	3.1803	6.3951	0.0715	0.0528	0.0964	0.1093	-0.226	0.2903	-0.0571	-0.3582	0.0359	0.0653	-0.0152	0.0174	0.118	-0.0102	0.1275	-8.0242	22.5978	-32.7575

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	chain 'B' and (resid 122 through 139 )	B	122 - 139
2	X-RAY DIFFRACTION	2	chain 'B' and (resid 140 through 144 )	B	140 - 144
3	X-RAY DIFFRACTION	3	chain 'B' and (resid 145 through 163 )	B	145 - 163
4	X-RAY DIFFRACTION	4	chain 'B' and (resid 164 through 168 )	B	164 - 168
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 42 through 51 )	A	42 - 51
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 52 through 60 )	A	52 - 60
7	X-RAY DIFFRACTION	7	chain 'A' and (resid 61 through 76 )	A	61 - 76
8	X-RAY DIFFRACTION	8	chain 'A' and (resid 77 through 96 )	A	77 - 96
9	X-RAY DIFFRACTION	9	chain 'A' and (resid 97 through 115 )	A	97 - 115
10	X-RAY DIFFRACTION	10	chain 'A' and (resid 116 through 121 )	A	116 - 121
11	X-RAY DIFFRACTION	11	chain 'A' and (resid 122 through 139 )	A	122 - 139
12	X-RAY DIFFRACTION	12	chain 'A' and (resid 140 through 144 )	A	140 - 144
13	X-RAY DIFFRACTION	13	chain 'A' and (resid 145 through 163 )	A	145 - 163
14	X-RAY DIFFRACTION	14	chain 'A' and (resid 164 through 168 )	A	164 - 168
15	X-RAY DIFFRACTION	15	chain 'B' and (resid 42 through 51 )	B	42 - 51
16	X-RAY DIFFRACTION	16	chain 'B' and (resid 52 through 60 )	B	52 - 60
17	X-RAY DIFFRACTION	17	chain 'B' and (resid 61 through 68 )	B	61 - 68
18	X-RAY DIFFRACTION	18	chain 'B' and (resid 69 through 80 )	B	69 - 80
19	X-RAY DIFFRACTION	19	chain 'B' and (resid 81 through 106 )	B	81 - 106
20	X-RAY DIFFRACTION	20	chain 'B' and (resid 107 through 121 )	B	107 - 121

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Yorodumi