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- PDB-5d3l: First bromodomain of BRD4 bound to inhibitor XD35 -

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Basic information

Entry
Database: PDB / ID: 5d3l
TitleFirst bromodomain of BRD4 bound to inhibitor XD35
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / Gene regulation / Bromodomain / Inhibitor
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 ...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 / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / transcription coactivator activity / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / chromatin remodeling / protein serine/threonine kinase activity / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / 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 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-57F / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsWohlwend, D. / Huegle, M.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationWO2012/1-1 Germany
CitationJournal: J.Med.Chem. / Year: 2016
Title: 4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1).
Authors: Hugle, M. / Lucas, X. / Weitzel, G. / Ostrovskyi, D. / Breit, B. / Gerhardt, S. / Einsle, O. / Gunther, S. / Wohlwend, D.
History
DepositionAug 6, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jan 20, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 9, 2016Group: Database references
Revision 1.2Sep 6, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5352
Polymers15,0991
Non-polymers4361
Water3,513195
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.580, 47.940, 58.320
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 15099.380 Da / Num. of mol.: 1 / Fragment: First bromodomain, UNP residues 42-168 / Mutation: T43M
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-57F / 4-acetyl-N-[5-(diethylsulfamoyl)-2-hydroxy-4-methylphenyl]-3-ethyl-5-methyl-1H-pyrrole-2-carboxamide


Mass: 435.537 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H29N3O5S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 195 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 1.92 Å3/Da / Density % sol: 36.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG3350, Bis-tris, ammonium acetate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Dec 5, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.5→37 Å / Num. obs: 18613 / % possible obs: 97.4 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.068 / Net I/σ(I): 9.6
Reflection shellResolution: 1.5→1.58 Å / Rmerge(I) obs: 0.183 / Mean I/σ(I) obs: 2.4 / Num. unique all: 2693 / % possible all: 98.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0071refinement
SCALA3.3.21data scaling
PHASERphasing
iMOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→37 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.949 / SU B: 2.741 / SU ML: 0.057 / Cross valid method: THROUGHOUT / ESU R: 0.094 / ESU R Free: 0.089 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20128 1850 10 %RANDOM
Rwork0.17631 ---
obs0.17881 16718 96.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 16.011 Å2
Baniso -1Baniso -2Baniso -3
1-1.06 Å2-0 Å2-0 Å2
2---1.42 Å2-0 Å2
3---0.36 Å2
Refinement stepCycle: 1 / Resolution: 1.5→37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1062 0 30 195 1287
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.021157
X-RAY DIFFRACTIONr_bond_other_d0.0010.021096
X-RAY DIFFRACTIONr_angle_refined_deg1.3621.9991585
X-RAY DIFFRACTIONr_angle_other_deg0.79132535
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8095134
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.6092655
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.87515203
X-RAY DIFFRACTIONr_dihedral_angle_4_deg26.865153
X-RAY DIFFRACTIONr_chiral_restr0.0750.2165
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211318
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02259
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.2490.671527
X-RAY DIFFRACTIONr_mcbond_other0.2480.671526
X-RAY DIFFRACTIONr_mcangle_it0.4241.007664
X-RAY DIFFRACTIONr_mcangle_other0.4241.008665
X-RAY DIFFRACTIONr_scbond_it0.3450.729630
X-RAY DIFFRACTIONr_scbond_other0.3440.73631
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.5451.083922
X-RAY DIFFRACTIONr_long_range_B_refined3.4297.3475105
X-RAY DIFFRACTIONr_long_range_B_other3.0656.6274875
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.5→1.539 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.249 137 -
Rwork0.214 1226 -
obs--96.39 %
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)
12.3809-0.77642.94931.44-1.18615.98820.06250.3155-0.0193-0.0591-0.064-0.09910.02010.4190.00150.00890.00840.01190.045-0.00060.029617.0563-8.9396-26.8132
21.1326-0.0848-1.40731.09641.7277.55290.0778-0.00620.2896-0.10710.01470.0116-0.2935-0.1693-0.09250.0154-0.00020.01380.0316-0.01470.0891-2.4623-1.8666-27.9674
37.0996-1.21924.13741.3209-0.51012.4568-0.114-0.26320.34560.2539-0.14780.2329-0.0387-0.21250.26170.0707-0.00230.04680.1041-0.07990.09795.5106-1.3127-10.9506
42.3694-0.38752.0041.4991-0.16532.6220.0133-0.05280.03760.1896-0.0022-0.13250.0590.0508-0.01110.0267-0.0002-0.01690.0161-0.00510.013613.0885-9.8267-18.8271
53.6794-2.16514.7953.9189-3.0496.79990.1339-0.1687-0.01950.1428-0.01890.2420.146-0.1501-0.1150.0245-0.02070.01920.0358-0.01410.02994.43-13.156-16.7879
64.0861-3.8095-2.81957.5426-0.20373.964-0.5995-0.5412-0.0951.49630.51040.0689-0.19950.33950.08910.4653-0.083-0.00320.24040.02010.01849.2294-14.4884-3.6263
73.3349-0.26474.19010.8182-0.20017.1997-0.0055-0.31210.1860.1333-0.09440.13040.1888-0.29180.09990.0657-0.02050.0480.1146-0.03540.119-6.1584-7.0266-15.8596
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 55
2X-RAY DIFFRACTION2A56 - 69
3X-RAY DIFFRACTION3A70 - 85
4X-RAY DIFFRACTION4A86 - 123
5X-RAY DIFFRACTION5A124 - 137
6X-RAY DIFFRACTION6A138 - 151
7X-RAY DIFFRACTION7A152 - 168

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