PDB-7vrz: crystal structure of BRD2-BD1 in complex with purine derivative

ID or keywords:

Entry

Database: PDB / ID: 7vrz

Title

crystal structure of BRD2-BD1 in complex with purine derivative

Components

Bromodomain-containing protein 2

BRD2

Keywords

TRANSCRIPTION / BET family /

BET inhibitor /

Bromodomain Inhibitor / BRD2-BD1 inhibitor

Function / homology

Function and homology information

chromatin looping / acetylation-dependent protein binding / RUNX3 regulates p14-ARF / positive regulation of T-helper 17 cell lineage commitment / protein localization to chromatin / neural tube closure / lysine-acetylated histone binding /

nucleosome assembly /

spermatogenesis / nuclear speck ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

MOLECULAR REPLACEMENT / Resolution: 2.05 Å

Authors

Padmanabhan, B. / Arole, A. / Deshmukh, P. / Ashok, S. / Mathur, S.

Funding support

1items

Citation

Journal: Acta Crystallogr D Struct Biol / Year: 2023
Title: Structural and biochemical insights into purine-based drug molecules in hBRD2 delineate a unique binding mode opening new vistas in the design of inhibitors of the BET family.
Authors: Arole, A.H. / Deshmukh, P. / Sridhar, A. / Mathur, S. / Mahalingaswamy, M. / Subramanya, H. / Dalavaikodihalli Nanjaiah, N. / Padmanabhan, B.

History

Deposition	Oct 25, 2021	Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0	Feb 1, 2023	Provider: repository / Type: Initial release
Revision 1.1	Aug 2, 2023	Group: Database references / Category: citation / citation_author Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _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 16, 2023	Group: Data collection / Database references Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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	Sep 27, 2023	Group: Derived calculations / Structure summary / Category: chem_comp / entity / pdbx_entity_nonpoly Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 1.4	Nov 29, 2023	Group: Refinement description / Category: pdbx_initial_refinement_model

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	7vrz.cif.gz	159.7 KB	Display	PDBx/mmCIF format
PDB format	pdb7vrz.ent.gz	126.1 KB	Display	PDB format
PDBx/mmJSON format	7vrz.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/vr/7vrz ftp://data.pdbj.org/pub/pdb/validation_reports/vr/7vrz	HTTPS FTP

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Related structure data

Related structure data	7vrhC 7vriC 7vrkC 7vrmC 7vroC 7vrqC 7vs0C 7vs1C 7vsfC 6jkeS 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	#122 - Feb 2010 Enhanceosome similarity (1)

Deposited unit

A: Bromodomain-containing protein 2

B: Bromodomain-containing protein 2

C: Bromodomain-containing protein 2

hetero molecules

45.9 kDa, 3 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Bromodomain-containing protein 2

B: Bromodomain-containing protein 2

hetero molecules

defined by author&software
Evidence: gel filtration
30.8 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

C: Bromodomain-containing protein 2

hetero molecules

C: Bromodomain-containing protein 2

hetero molecules

defined by author&software
30.3 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	114.665, 55.822, 67.765
Angle α, β, γ (deg.)	90.00, 94.07, 90.00
Int Tables number	5
Space group name H-M	C121

Components on special symmetry positions

ID	Model	Components
1	1	C-338- HOH

#1: Protein	Bromodomain-containing protein 2 / BRD2 Mass: 14885.340 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: BRD2 / Plasmid: pET28a / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P25440
#2: Chemical	ChemComp-7UH / Doxofylline / 7-(1,3-dioxolan-2-ylmethyl)-1,3-dimethyl-purine-2,6-dione Mass: 266.253 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₁₁H₁₄N₄O₄ / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-SO4 / SULFATE ION / Sulfate Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO₄
#4: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 237 / 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: 2.26 Å³/Da / Density % sol: 45.5 %
Crystal grow	Temperature: 300 K / Method: vapor diffusion, hanging drop / Details: PEG MME 5000, 0.1M MES

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54056 Å
Detector	Type: RIGAKU HyPix-6000HE / Detector: PIXEL / Date: Nov 26, 2020
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1.54056 Å / Relative weight: 1
Reflection	Resolution: 2.05→31.48 Å / Num. obs: 26960 / % possible obs: 99 % / Redundancy: 3.8 % / B_iso Wilson estimate: 11.04 Å² / CC_1/2: 1 / R_merge(I) obs: 0.091 / Net I/σ(I): 20.69
Reflection shell	Resolution: 2.05→2.09 Å / Redundancy: 2 % / R_merge(I) obs: 0.27 / Num. unique obs: 1208 / CC_1/2: 0.96 / % possible all: 90

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Processing

Software

Name	Version	Classification
PHENIX	(1.18_3855: ???)	refinement
HKL-3000		data reduction
HKL-2000		data scaling
PHENIX		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 6JKE

6jke

Resolution: 2.05→31.48 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.83 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.2122	1325	4.95 %
R_work	0.1746	-	-
obs	0.1765	26755	99.16 %

Solvent computation

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

Refinement step

Cycle: LAST / Resolution: 2.05→31.48 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2693	0	86	237	3016

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.008	2892
X-RAY DIFFRACTION	f_angle_d	0.796	3928
X-RAY DIFFRACTION	f_dihedral_angle_d	5.093	421
X-RAY DIFFRACTION	f_chiral_restr	0.045	406
X-RAY DIFFRACTION	f_plane_restr	0.006	549

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 (%)
2.05-2.13	0.258	128	0.2116	2670	X-RAY DIFFRACTION	95
2.13-2.23	0.2443	148	0.1877	2767	X-RAY DIFFRACTION	99
2.23-2.35	0.233	154	0.1844	2860	X-RAY DIFFRACTION	100
2.35-2.49	0.2412	142	0.1782	2808	X-RAY DIFFRACTION	100
2.49-2.69	0.218	146	0.1821	2846	X-RAY DIFFRACTION	100
2.69-2.96	0.2496	151	0.1933	2848	X-RAY DIFFRACTION	100
2.96-3.38	0.2347	153	0.1862	2839	X-RAY DIFFRACTION	100
3.38-4.26	0.1734	146	0.1533	2879	X-RAY DIFFRACTION	100
4.26-31.48	0.1928	157	0.1654	2913	X-RAY DIFFRACTION	100

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	0.4143	-0.3395	0.0746	0.445	-0.0594	0.3691	0.3584	-1.0148	-0.8838	0.0739	-0.0715	0.6679	0.1915	-0.8507	0.0197	0.3126	-0.0522	0.0926	0.5298	0.1225	0.4689	3.825	4.974	82.447
2	0.3974	-0.3133	0.0086	0.1518	0.0063	0.2206	-0.0312	0.0687	-0.0148	0.0745	0.0198	0.1776	-0.0407	-0.2368	0	0.2055	0.0248	0.0264	0.2584	0.0016	0.2998	6.528	14.96	70.556
3	0.5158	0.5955	0.0465	0.6503	0.0739	0.3072	0.1627	0.59	-0.0544	-0.2079	-0.3719	0.2322	0.1262	-0.1857	-0.0004	0.3089	0.0534	-0.0229	0.4069	-0.0068	0.2929	11.472	7.356	55.8
4	0.6405	0.2051	0.2977	1.1346	-0.7769	1.2228	-0.095	0.1965	-0.5221	-0.0757	-0.1689	0.4127	0.4432	-0.3661	0.0003	0.2725	-0.0183	0.0165	0.2231	-0.0316	0.3264	10.819	0.955	64.532
5	0.1277	-0.1518	-0.164	0.3568	0.4594	0.6248	-0.2335	-0.3931	-1.1824	0.8767	0.2552	0.6648	1.6605	0.3065	0.0085	0.5367	-0.0219	0.2191	0.4489	0.0925	0.7584	4.477	-4.137	76.379
6	2.8717	-1.3631	0.6143	2.2544	1.0855	1.3316	-0.2065	-0.1399	-0.2333	0.0072	-0.0218	-0.0106	0.1607	-0.0128	0.0005	0.2167	0.0053	0.0005	0.1935	-0.0059	0.2331	18.157	6.073	67.282
7	2.2412	-0.2628	0.1292	1.319	1.0163	0.9235	-0.0284	-0.3845	0.1093	0.3325	-0.0702	-0.0595	-0.2341	0.1839	0.0005	0.2747	0.0187	0.0045	0.2242	-0.0001	0.2925	15.653	13.751	74.042
8	1.9998	5.1238	1.2546	2.0003	2.7743	2.0002	0.152	-1.2808	-1.7843	1.1506	0.9417	1.5753	7.437	1.4454	-0.868	0.7236	0.1595	0.2846	0.7631	0.6276	0.8477	9.838	0.674	90.607
9	1.6824	-0.5674	0.2881	0.765	0.1205	0.1034	0.1144	-1.749	0.4789	1.6909	0.129	-0.1169	0.114	-0.3141	0.0145	0.5419	-0.052	0.0051	0.594	-0.0318	0.2795	24.126	10.046	91.911
10	0.6737	0.3047	-0.0274	0.5664	-0.0697	0.2702	-0.1462	-0.3842	-0.0593	0.3935	0.1224	-0.0601	0.3062	0.1966	0.0007	0.3674	0.0396	-0.0551	0.2662	-0.017	0.2784	33.08	1.031	81.416
11	0.2018	0.0251	-0.02	0.4957	0.3806	0.1962	0.4165	0.118	0.1437	-0.1532	-0.0854	-0.5391	0.3422	0.9412	0.0028	0.2896	0.0576	0.03	0.47	-0.0231	0.4679	42.19	10.141	69.761
12	1.3989	-0.1817	-0.645	0.9755	0.7065	0.6292	0.149	-0.1943	0.1579	0.2464	0.1263	-0.5062	-0.4882	0.2119	-0.0009	0.3503	-0.0557	-0.043	0.2301	-0.0081	0.3388	34.052	15.14	75.905
13	0.2291	0.1657	-0.1661	0.1435	-0.0848	0.2436	0.319	-0.1241	1.5727	0.9602	-0.3038	0.3831	-1.5195	-0.0207	0.0083	0.6439	-0.0458	-0.0808	0.3813	0.0081	0.4727	28.106	20.258	88.137
14	1.3364	0.0067	0.7704	1.9392	-1.3413	1.5549	0.0858	-0.1767	0.07	0.0131	-0.0129	-0.1739	-0.1289	0.0288	-0.0007	0.2138	-0.0223	-0.0357	0.1814	0.0033	0.2598	27.656	9.513	72.031
15	1.4587	0.54	0.7032	1.4272	-0.7044	1.4004	0.0168	-0.1638	-0.1751	0.1702	-0.0935	0.2378	0.149	-0.4305	-0.0003	0.2661	-0.018	0.0013	0.2385	0.0033	0.2662	23.378	2.128	78.489
16	0.261	0.1148	0.0505	0.0566	0.0041	0.0841	-0.4443	0.6541	0.9595	-0.4247	0.0095	-0.5234	-1.7633	-0.1808	0.0007	0.6317	-0.0195	-0.0285	0.4253	0.0584	0.4366	-6.984	34.171	90.051
17	0.3306	-0.2898	0.0586	0.2743	-0.0948	0.0424	0.0913	0.1743	1.1608	-0.6038	0.1052	-0.7472	-0.1779	0.1924	-0.0008	0.3705	-0.1181	0.0573	0.4235	0.0412	0.3828	0.089	25.761	87.591
18	0.0097	-0.0599	-0.0143	0.5939	-0.0732	0.0075	0.5948	0.1583	-0.1119	-1.0131	-0.106	0.1512	-0.0044	0.7376	0.003	0.198	0.0108	0.1372	0.4556	-0.0637	0.2346	2.748	15.202	88.542
19	0.2287	-0.231	-0.001	0.283	0.1257	0.1389	0.0331	-0.058	-0.4675	-0.6577	0.1191	-0.5633	1.0011	0.5602	-0.0002	0.6599	-0.0102	-0.0476	0.4905	-0.0813	0.4433	-7.882	5.939	84.3
20	1.0223	-0.4605	0.8624	1.0837	0.4987	1.2145	-0.1189	0.4204	-0.0358	-0.6548	0.2461	0.3084	0.1896	-0.1074	-0.0002	0.3132	-0.0511	-0.0474	0.3874	0.025	0.2683	-12.441	15.895	87.685
21	0.1138	0.0313	0.0225	0.1444	0.0673	0.0006	-0.4487	-0.4211	0.1512	-0.273	0.4128	0.6015	-0.2165	0.1516	-0.0006	0.3423	0.0697	-0.0198	0.4553	0.0664	0.37	-16.874	29.764	86.786
22	0.9566	0.6051	0.0046	0.4953	0.0301	2.1557	0.0072	0.0824	-0.0846	-0.2889	0.1061	0.3572	-0.1175	-0.1646	-0.0001	0.2105	0.0001	-0.0134	0.3485	0.0223	0.1866	-9.966	17.755	95.457
23	-0.0003	0.0298	0.02	0.1249	0.0649	0.0934	0.0124	0.4092	-0.6393	-0.6425	0.2965	-0.0356	1.1713	0.2151	0.0111	0.4033	0.102	-0.0598	0.3483	-0.0562	0.3682	-0.906	3.643	97.462
24	2.3877	1.2299	0.2076	0.8019	-0.457	2.9727	0.0254	0.0303	0.1601	0.1883	-0.0611	-0.4902	-0.2867	0.2704	0.0002	0.2289	0.0066	0.0271	0.3718	-0.01	0.2483	-0.922	22.321	97.682

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	( CHAIN A AND RESID 75:84 )	A	75 - 84
2	X-RAY DIFFRACTION	2	( CHAIN A AND RESID 85:96 )	A	85 - 96
3	X-RAY DIFFRACTION	3	( CHAIN A AND RESID 97:112 )	A	97 - 112
4	X-RAY DIFFRACTION	4	( CHAIN A AND RESID 113:131 )	A	113 - 131
5	X-RAY DIFFRACTION	5	( CHAIN A AND RESID 132:137 )	A	132 - 137
6	X-RAY DIFFRACTION	6	( CHAIN A AND RESID 138:160 )	A	138 - 160
7	X-RAY DIFFRACTION	7	( CHAIN A AND RESID 161:182 )	A	161 - 182
8	X-RAY DIFFRACTION	8	( CHAIN A AND RESID 183:183 )	A	183
9	X-RAY DIFFRACTION	9	( CHAIN B AND RESID 76:84 )	B	76 - 84
10	X-RAY DIFFRACTION	10	( CHAIN B AND RESID 85:99 )	B	85 - 99
11	X-RAY DIFFRACTION	11	( CHAIN B AND RESID 100:112 )	B	100 - 112
12	X-RAY DIFFRACTION	12	( CHAIN B AND RESID 113:131 )	B	113 - 131
13	X-RAY DIFFRACTION	13	( CHAIN B AND RESID 132:137 )	B	132 - 137
14	X-RAY DIFFRACTION	14	( CHAIN B AND RESID 138:160 )	B	138 - 160
15	X-RAY DIFFRACTION	15	( CHAIN B AND RESID 161:182 )	B	161 - 182
16	X-RAY DIFFRACTION	16	( CHAIN C AND RESID 76:84 )	C	76 - 84
17	X-RAY DIFFRACTION	17	( CHAIN C AND RESID 85:92 )	C	85 - 92
18	X-RAY DIFFRACTION	18	( CHAIN C AND RESID 93:99 )	C	93 - 99
19	X-RAY DIFFRACTION	19	( CHAIN C AND RESID 100:112 )	C	100 - 112
20	X-RAY DIFFRACTION	20	( CHAIN C AND RESID 113:131 )	C	113 - 131
21	X-RAY DIFFRACTION	21	( CHAIN C AND RESID 132:137 )	C	132 - 137
22	X-RAY DIFFRACTION	22	( CHAIN C AND RESID 138:155 )	C	138 - 155
23	X-RAY DIFFRACTION	23	( CHAIN C AND RESID 156:160 )	C	156 - 160
24	X-RAY DIFFRACTION	24	( CHAIN C AND RESID 161:182 )	C	161 - 182

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