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- PDB-6duv: Crystal structure of the second bromodomain of human BRD4 in comp... -

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Basic information

Entry
Database: PDB / ID: 6duv
TitleCrystal structure of the second bromodomain of human BRD4 in complex with MS417 inhibitor
ComponentsBromodomain-containing protein 4BRD4
KeywordsPROTEIN BINDING/Inhibitor / protein-small molecule inhibitor complex / PROTEIN BINDING / PROTEIN BINDING-Inhibitor complex
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 ...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 / transcription coregulator activity / lysine-acetylated histone binding / p53 binding / chromosome / regulation of inflammatory response / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus
Similarity search - Function
Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-0S6 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.8 Å
AuthorsBabault, N. / Zhou, M.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01HG004508 United States
CitationJournal: To be published
Title: Role of Bound Water Molecules in Differential Recognition of Di-Acetylated Histone Peptides by the BRD4 Bromodomains
Authors: Babault, N. / Zhang, Q. / Zhang, G. / Zhou, M.M. / Zeng, L.
History
DepositionJun 22, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 26, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,75412
Polymers26,0742
Non-polymers1,67910
Water3,423190
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,9915
Polymers13,0371
Non-polymers9544
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,7627
Polymers13,0371
Non-polymers7256
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.580, 74.580, 111.470
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 350 through 355 or resid 357...
21(chain B and (resid 350 through 355 or resid 357...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11VALVALLYSLYS(chain A and (resid 350 through 355 or resid 357...AA350 - 3554 - 9
12CYSCYSLEULEU(chain A and (resid 350 through 355 or resid 357...AA357 - 38711 - 41
13ASPASPPHEPHE(chain A and (resid 350 through 355 or resid 357...AA389 - 42643 - 80
14ASNASNPROPRO(chain A and (resid 350 through 355 or resid 357...AA428 - 43582 - 89
15HISHISALAALA(chain A and (resid 350 through 355 or resid 357...AA437 - 44391 - 97
16LYSLYSPROPRO(chain A and (resid 350 through 355 or resid 357...AA445 - 45899 - 112
21VALVALLYSLYS(chain B and (resid 350 through 355 or resid 357...BB350 - 3554 - 9
22CYSCYSLEULEU(chain B and (resid 350 through 355 or resid 357...BB357 - 38711 - 41
23ASPASPPHEPHE(chain B and (resid 350 through 355 or resid 357...BB389 - 42643 - 80
24ASNASNPROPRO(chain B and (resid 350 through 355 or resid 357...BB428 - 43582 - 89
25HISHISALAALA(chain B and (resid 350 through 355 or resid 357...BB437 - 44391 - 97
26LYSLYSPROPRO(chain B and (resid 350 through 355 or resid 357...BB445 - 45899 - 112

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Components

#1: Protein Bromodomain-containing protein 4 / BRD4 / Protein HUNK1


Mass: 13037.170 Da / Num. of mol.: 2 / Fragment: BRD4 second bromodomain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pET28a-LIC / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) codon plus RIL / References: UniProt: O60885
#2: Chemical ChemComp-0S6 / methyl [(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate


Mass: 414.908 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C20H19ClN4O2S
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 190 / Source method: isolated from a natural source / Formula: H2O
Compound detailsonly one domain crystallized at the N-terminus and the C-terminus has been either cleaved or ...only one domain crystallized at the N-terminus and the C-terminus has been either cleaved or disorder in the crystal
Sequence detailsThe following sequence was probably cleaved during crystallization ...The following sequence was probably cleaved during crystallization DEPEEPVVAVSSPAVPPPTKVVAPPSSSDSSSDSSSDSDSSTDDSEEE RAQRLAELQEQLKAVHEQLAALSQPQQNKPKKKEKDKKEKKKEKHKRKEEVEENKKSKAKEPPPKKTKKNNSSNSNVSKK EPAPMKSKPPPTYESEEEDKCKPMSYEEKRQLSLDINKLPGEKLGRVVHIIQSREPSLKNSNPDEIEIDFETLKPSTLRE LERYVTSCLRKKRKPQAEKVDVIAGSS

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.43 Å3/Da / Density % sol: 64.16 % / Mosaicity: 0.78 °
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 10.5
Details: 2.0 Ammonium Sulfate, 0.2 M Lithium Sulfate, CAPS pH10.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X6A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Feb 19, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→64.588 Å / Num. obs: 33150 / % possible obs: 97.8 % / Redundancy: 9.9 % / Biso Wilson estimate: 23.22 Å2 / Rpim(I) all: 0.022 / Rrim(I) all: 0.071 / Rsym value: 0.068 / Net I/av σ(I): 8.8 / Net I/σ(I): 20.8 / Num. measured all: 327247
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
1.8-1.96.50.5021.52757542300.2060.5450.5023.386.8
1.9-2.0190.3612.14069345170.1250.3830.3615.897.9
2.01-2.1510.70.2333.34660543390.0740.2450.23310.1100
2.15-2.3210.80.164.74376040690.0510.1680.1614.4100
2.32-2.5510.80.1136.64034437520.0360.1190.11318.4100
2.55-2.8510.70.088.93650134020.0250.0840.0825.7100
2.85-3.2910.70.05711.63232530290.0180.060.05735.1100
3.29-4.0310.60.04215.22731025810.0130.0440.04248.6100
4.03-5.6910.30.03517.12100520420.0110.0370.03550.8100
5.69-42.1969.40.0318.51112911890.010.0320.0344.999.7

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Processing

Software
NameVersionClassification
SCALA3.3.20data scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.24data extraction
iMOSFLMdata reduction
PHASERphasing
RefinementResolution: 1.8→42.196 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 16.88 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.188 1682 5.08 %
Rwork0.1602 31427 -
obs0.1616 33109 97.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 100.02 Å2 / Biso mean: 30.0653 Å2 / Biso min: 10.79 Å2
Refinement stepCycle: final / Resolution: 1.8→42.196 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1785 0 112 190 2087
Biso mean--26.67 37.22 -
Num. residues----219
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071987
X-RAY DIFFRACTIONf_angle_d1.6252677
X-RAY DIFFRACTIONf_chiral_restr0.048260
X-RAY DIFFRACTIONf_plane_restr0.007341
X-RAY DIFFRACTIONf_dihedral_angle_d7.2111645
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A978X-RAY DIFFRACTION4.878TORSIONAL
12B978X-RAY DIFFRACTION4.878TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8001-1.85310.22471140.23552222233684
1.8531-1.91290.23931350.20822405254091
1.9129-1.98120.21351340.18892576271098
1.9812-2.06060.20331360.161226432779100
2.0606-2.15430.16141410.157126492790100
2.1543-2.26790.17891410.157726762817100
2.2679-2.410.21421460.159826492795100
2.41-2.5960.20251570.160126402797100
2.596-2.85720.19191490.163326962845100
2.8572-3.27060.18261430.166426852828100
3.2706-4.120.17291430.143227232866100
4.12-42.20780.17951430.152728633006100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°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)
10.6124-0.21980.14070.9332-0.52520.9416-0.05180.1640.0032-0.11990.09390.1136-0.06830.0382-0.00010.1439-0.0230.00090.1441-0.01510.1412-40.305414.59677.4084
20.2231-0.1623-0.10491.1662-0.28340.49810.05290.05670.0078-0.05390.01780.03880.2630.04480.00010.18530.0157-0.02160.14070.00030.1564-36.539.78686.6361
30.6867-0.08590.05750.6693-0.62770.6138-0.0229-0.12040.0269-0.1829-0.08-0.37460.16380.1577-0.06290.21980.05170.00010.17230.00880.2528-23.2495-8.069611.6425
41.2201-0.2047-0.0341.7003-0.65090.4965-0.0595-0.03530.1191-0.4891-0.0237-0.19180.00820.0372-0.02470.2480.04020.0290.125-0.00260.1685-26.1475-2.986.9988
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 349 through 399 )A349 - 399
2X-RAY DIFFRACTION2chain 'A' and (resid 400 through 458 )A400 - 458
3X-RAY DIFFRACTION3chain 'B' and (resid 350 through 389 )B350 - 389
4X-RAY DIFFRACTION4chain 'B' and (resid 390 through 458 )B390 - 458

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