PDB-6vuf: Crystal structure of BRD4 bromodomain 1 with N-methylpyrrolidin-2...

ID or keywords:

Entry

Database: PDB / ID: 6vuf

Title

Crystal structure of BRD4 bromodomain 1 with N-methylpyrrolidin-2-one (NMP) derivative 7h (4-(1-methyl-5-oxopyrrolidin-3-yl)-N-propylbenzenesulfonamide)

Components

Bromodomain-containing protein 4

Keywords

PROTEIN BINDING / BRD4 BD1 / Bromodomain / NMP

Function / homology

Function and homology information

RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.59 Å

Authors

Ilyichova, O.V. / Scanlon, M.J. / Thompson, P.E.

Citation

Journal: Eur.J.Med.Chem. / Year: 2020
Title: Substituted 1-methyl-4-phenylpyrrolidin-2-ones - Fragment-based design of N-methylpyrrolidone-derived bromodomain inhibitors.
Authors: Hilton-Proctor, J.P. / Ilyichova, O. / Zheng, Z. / Jennings, I.G. / Johnstone, R.W. / Shortt, J. / Mountford, S.J. / Scanlon, M.J. / Thompson, P.E.

History

Deposition	Feb 15, 2020	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Feb 26, 2020	Provider: repository / Type: Initial release
Revision 1.1	Mar 18, 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 / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2	Oct 11, 2023	Group: Data collection / Database references / Refinement description Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	6vuf.cif.gz	156.1 KB	Display	PDBx/mmCIF format
PDB format	pdb6vuf.ent.gz	100.5 KB	Display	PDB format
PDBx/mmJSON format	6vuf.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	6vuf_validation.pdf.gz	370.4 KB	Display	wwPDB validaton report
Full document	6vuf_full_validation.pdf.gz	373.7 KB	Display
Data in XML	6vuf_validation.xml.gz	2.2 KB	Display
Data in CIF	6vuf_validation.cif.gz	7.6 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/vu/6vuf ftp://data.pdbj.org/pub/pdb/validation_reports/vu/6vuf	HTTPS FTP

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Related structure data

Related structure data	6vubC 6vucC 6vujC 5dw2S S: Starting model for refinement C: citing same article (ref.)
Similar structure data	5ti5-d 6ckr-1 6v1l-d 6wgx-1 3uvx-d 6xv3-2 5d3j-d 4bw2-d 6tpx-d 6vuc-d 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

Deposited unit

A: Bromodomain-containing protein 4

B: Bromodomain-containing protein 4

hetero molecules

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

1

A: Bromodomain-containing protein 4

hetero molecules

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

2

B: Bromodomain-containing protein 4

hetero molecules

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

Unit cell

Length a, b, c (Å)	36.030, 79.205, 46.819
Angle α, β, γ (deg.)	90.000, 92.820, 90.000
Int Tables number	4
Space group name H-M	P12₁1
Space group name Hall	P2yb
Symmetry operation	#1: x,y,z #2: -x,y+1/2,-z

#1: Protein	Bromodomain-containing protein 4 / Protein HUNK1 Mass: 14968.182 Da / Num. of mol.: 2 / Fragment: bromodomain 1 (UNP residues 44-168) Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pET28(a) / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: O60885
#2: Chemical	ChemComp-RLV / 4-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]-N-propylbenzene-1-sulfonamide Mass: 296.385 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₄H₂₀N₂O₃S / Feature type: SUBJECT OF INVESTIGATION
#3: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 425 / 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: 2.21 Å³/Da / Density % sol: 44.33 %
Crystal grow	Temperature: 277.15 K / Method: vapor diffusion, hanging drop Details: 0.2 M sodium nitrate, 35% PEG3350, 6% v/v ethylene glycol

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.9537 Å
Detector	Type: ADSC QUANTUM 210r / Detector: CCD / Date: May 5, 2017
Radiation	Monochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.9537 Å / Relative weight: 1
Reflection	Resolution: 1.59→46.76 Å / Num. obs: 35273 / % possible obs: 99.8 % / Redundancy: 4.2 % / B_iso Wilson estimate: 14.82 Å² / CC_1/2: 0.997 / R_merge(I) obs: 0.079 / R_pim(I) all: 0.044 / Net I/σ(I): 10.3
Reflection shell	Resolution: 1.59→1.68 Å / R_merge(I) obs: 0.642 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 5067 / CC_1/2: 0.765 / R_pim(I) all: 0.357

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Processing

Software

Name	Version	Classification
PHENIX	1.16_3549	refinement
XDS		data reduction
SCALA		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: PDB entry 5DW2

5dw2

Resolution: 1.59→40.27 Å / SU ML: 0.2533 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.1124

	R_factor	Num. reflection	% reflection
R_free	0.2694	1770	5.06 %
R_work	0.2156	-	-
obs	0.2183	34946	98.92 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å

Displacement parameters

B_iso mean: 19.83 Å²

Refinement step

Cycle: LAST / Resolution: 1.59→40.27 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2082	0	39	425	2546

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.0084	2228
X-RAY DIFFRACTION	f_angle_d	0.9511	3053
X-RAY DIFFRACTION	f_chiral_restr	0.0476	328
X-RAY DIFFRACTION	f_plane_restr	0.0057	393
X-RAY DIFFRACTION	f_dihedral_angle_d	5.8093	1897

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 (%)
1.59-1.63	0.3551	140	0.3068	2491	X-RAY DIFFRACTION	97.05
1.63-1.68	0.3316	141	0.2588	2574	X-RAY DIFFRACTION	100
1.68-1.73	0.3222	136	0.2556	2561	X-RAY DIFFRACTION	99.96
1.73-1.8	0.2476	131	0.2375	2586	X-RAY DIFFRACTION	99.96
1.8-1.87	0.3077	140	0.2375	2545	X-RAY DIFFRACTION	100
1.87-1.95	0.4465	130	0.3647	2407	X-RAY DIFFRACTION	93.31
1.95-2.06	0.2896	133	0.2341	2565	X-RAY DIFFRACTION	99.74
2.06-2.19	0.2465	149	0.2052	2561	X-RAY DIFFRACTION	100
2.19-2.35	0.3607	133	0.272	2498	X-RAY DIFFRACTION	96.34
2.35-2.59	0.23	136	0.2094	2576	X-RAY DIFFRACTION	100
2.59-2.97	0.2729	124	0.1958	2595	X-RAY DIFFRACTION	100
2.97-3.74	0.2174	148	0.1715	2570	X-RAY DIFFRACTION	100
3.74-40.27	0.2004	129	0.1635	2647	X-RAY DIFFRACTION	99.61

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	0.500785166208	-0.311681249447	0.162095600661	1.25810152265	1.295759172	1.70771231811	0.0299219122255	0.104013457743	0.0203408564646	0.283098931806	-0.0036272715427	0.0105958526627	-0.229583645014	-0.179318266393	-0.0707445882969	0.245340804664	-0.0052589476309	0.00475883215398	0.133023473307	0.00272408321701	0.151927461158	13.1750441349	-21.3901177914	22.4175882316
2	4.22367406804	1.58485257109	5.27677690436	4.79305156239	-0.991301847252	9.05342909827	-0.314567989782	-0.251324936369	-0.015976385661	-0.00705010624603	0.085803653218	-0.0465840508492	-0.073704024013	-0.0357555803013	0.194956308099	0.137600498386	0.0581732685853	0.049754245399	0.189980865871	0.00227687126437	0.142867606381	19.2054448802	-14.0895842732	8.25487703001
3	1.24957568819	0.13919631498	-0.444180862806	1.70399375981	1.38626559536	2.01118595481	-0.107866464555	-0.0576367475047	0.0596067462101	0.0858391186188	0.150285219682	-0.0661968980452	0.3467451886	0.184284231687	-0.0558863310273	0.164140106067	0.0107755277183	-0.0032394900311	0.102799235221	-0.000758731487416	0.112805973961	15.0872881328	-7.8972045636	24.4195314056
4	2.49113559192	-2.01074332259	-2.07012566418	6.32641987541	3.1728548994	3.75911420392	0.0715129752564	0.250260653333	0.0345968043446	-0.284297842271	-0.138735392896	0.133630494549	-0.161661577349	-0.24195357973	0.0854302613934	0.115434651903	-0.0216200301443	-0.00328546711302	0.131461791286	0.0218437541143	0.0775679573	7.64047180034	-3.48309600443	20.6335143095
5	1.43029008985	0.164613408497	0.64628169234	7.60897055427	7.61908971895	8.95034024882	-0.0830380927423	0.171361121599	0.0923460583276	-0.10909251641	-0.124609949728	0.0274982434416	-0.0204264506897	0.310364027683	0.15643283443	0.124762508353	-0.0100758287906	-0.000246756549812	0.120803135102	0.0410876970049	0.109328581279	13.6239378655	1.26292746809	14.3967057051
6	7.4598058493	6.4700370714	4.33002636439	6.22224793285	3.62398622436	5.6230508436	-0.307329627074	0.442715199692	-0.114106161494	-0.861056491293	0.235047293259	-0.550714095095	0.0604889535459	-0.106627033332	0.0331265557074	0.161868074314	-0.0057999939076	0.0758011696819	0.287843282596	0.0258421189253	0.175888453882	15.3847926073	-12.4728820916	1.16542176513
7	1.06882790629	-0.696297088002	-0.0797288305077	2.46067439833	-0.266270874838	1.39192692306	-0.0813564974838	-0.0578638659859	0.105511942163	0.27843643035	0.130110143578	0.0350456632015	-0.0925852014748	-0.0134231511832	-0.0741235160309	0.172722196818	0.0049881121175	0.00907131007065	0.101939868283	0.0153272822978	0.141282872049	-3.20797613815	22.4837287785	0.862426131296
8	6.84988589645	-1.88126574568	-5.89434056759	3.80877336657	1.90134062353	6.99972876803	-0.333442065523	-0.744047652919	0.204655535426	0.705424732084	0.488206369451	-0.432360917642	-0.118708872114	0.384136487155	-0.20068806291	0.329463055557	0.0405284487327	-0.0621817167837	0.208174752938	-0.0157775611258	0.106331809434	3.91046229805	15.2362145623	15.1630040132
9	2.77442937437	-0.268930291536	-2.5569532972	5.34127483791	3.91194447804	6.10762740402	0.240642785144	-0.104413974399	-0.0950346944433	0.314898416181	0.197705788508	-0.981639080093	0.244174266552	-0.27845719965	-0.217534614961	0.140368068744	0.0406081333499	-0.0361303654299	0.120359978395	0.00800226422137	0.13091734246	7.34318892311	7.17855936956	8.25865102066
10	0.655291756601	0.489258074825	0.625358670923	0.704361097235	-0.653890986163	2.537484995	0.00905473428889	0.12913538281	-0.231376349259	-0.0646366015655	-0.0158976401555	0.0257488182002	0.0975394494154	0.191654296354	0.000913428184236	0.0644569600469	0.0311556297746	0.00205674184752	0.101291103754	-0.00535586703226	0.121288743047	0.738135121138	2.66235292745	-6.52964880736
11	1.39976426102	1.88404233151	1.90296340126	3.38523414537	2.80949605753	3.86695569791	-0.050072922746	0.0666877121504	0.067145383431	0.025299883614	0.0149105013946	0.00233736126604	-0.130369339883	-0.012118227978	-0.0032413195256	0.0823509061099	0.0235039906037	0.00384056384566	0.115223057008	0.0319057608802	0.0859647571294	-3.87297926563	11.8852630152	-2.03227210278
12	0.54740370393	0.868775776979	0.452834807835	5.40645397372	1.81252694587	2.22015855847	-0.0327574386414	-0.000340411198407	0.0489606414844	0.258185813011	0.042215161443	0.108813899226	-0.178428727846	-0.171087738921	0.0127664229179	0.150614231591	0.0513294816706	0.0212212328008	0.118275274082	0.0256859000633	0.114473270587	-6.35222760122	11.6127306382	5.50079185684
13	6.56858965765	1.65274265905	-5.74483172912	6.1126926754	-1.01125680663	5.06142091575	-0.269580547192	-0.0638101384448	-1.04658259558	-0.222050238733	0.169959473089	0.889874766802	0.701096347622	-0.564640159966	0.167177023965	0.117829301321	-0.0457790776981	0.0214308810768	0.154867028658	0.0321045526595	0.314923827769	-9.16504504555	-6.72868733522	-3.36588585713
14	2.54996811965	0.523259692033	0.471219228476	4.81153711821	3.904694359	5.08737563221	-0.0618807479836	-0.24747308651	0.00642365299031	0.514075379992	0.0577402774092	-0.0234858203176	0.229115112434	-0.13937877562	0.0109105500713	0.134341695546	0.0466441844338	-0.00849377525788	0.123581252782	0.0248034518335	0.119769095182	-1.51432411591	2.28614506039	11.465748723

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 43 through 60 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 61 through 68 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 69 through 121 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 122 through 144 )
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 145 through 162 )
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 163 through 168 )
7	X-RAY DIFFRACTION	7	chain 'B' and (resid 43 through 60 )
8	X-RAY DIFFRACTION	8	chain 'B' and (resid 61 through 68 )
9	X-RAY DIFFRACTION	9	chain 'B' and (resid 69 through 76 )
10	X-RAY DIFFRACTION	10	chain 'B' and (resid 77 through 96 )
11	X-RAY DIFFRACTION	11	chain 'B' and (resid 97 through 115 )
12	X-RAY DIFFRACTION	12	chain 'B' and (resid 116 through 139 )
13	X-RAY DIFFRACTION	13	chain 'B' and (resid 140 through 144 )
14	X-RAY DIFFRACTION	14	chain 'B' and (resid 145 through 167 )

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