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- PDB-6u8m: BRD4-BD1 in complex with the cyclic peptide 3.2_1 -

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Basic information

Entry
Database: PDB / ID: 6u8m
TitleBRD4-BD1 in complex with the cyclic peptide 3.2_1
Components
  • Bromodomain-containing protein 4
  • cyclic peptide 3.2_1
KeywordsTRANSCRIPTION/INHIBITOR / BET / bromodomain / macrocyclic peptide / BRD4 / inhibitor / RaPID / TRANSCRIPTION-INHIBITOR complex / TRANSCRIPTION
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 / chromatin / 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, conserved site / Bromodomain signature. ...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, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
AMINO GROUP / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsPatel, K. / Walshe, J.L. / Walport, L.J. / Mackay, J.P.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP1161623 Australia
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2020
Title: Cyclic peptides can engage a single binding pocket through highly divergent modes.
Authors: Patel, K. / Walport, L.J. / Walshe, J.L. / Solomon, P.D. / Low, J.K.K. / Tran, D.H. / Mouradian, K.S. / Silva, A.P.G. / Wilkinson-White, L. / Norman, A. / Franck, C. / Matthews, J.M. / Guss, ...Authors: Patel, K. / Walport, L.J. / Walshe, J.L. / Solomon, P.D. / Low, J.K.K. / Tran, D.H. / Mouradian, K.S. / Silva, A.P.G. / Wilkinson-White, L. / Norman, A. / Franck, C. / Matthews, J.M. / Guss, J.M. / Payne, R.J. / Passioura, T. / Suga, H. / Mackay, J.P.
History
DepositionSep 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 3, 2021Group: 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
Revision 1.2Oct 11, 2023Group: 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 / 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
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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
C: cyclic peptide 3.2_1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4934
Polymers36,4773
Non-polymers161
Water3,855214
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.834, 72.616, 86.056
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

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
11THRTHRTHRTHR(chain 'A' and (resid 60 or resid 62 through 63...AA6025
12GLNGLNLEULEU(chain 'A' and (resid 60 or resid 62 through 63...AA62 - 6327 - 28
13TYRTYRLEULEU(chain 'A' and (resid 60 or resid 62 through 63...AA65 - 6730 - 32
14VALVALTRPTRP(chain 'A' and (resid 60 or resid 62 through 63...AA69 - 7534 - 40
15HISHISLYSLYS(chain 'A' and (resid 60 or resid 62 through 63...AA77 - 11142 - 76
16ARGARGASNASN(chain 'A' and (resid 60 or resid 62 through 63...AA113 - 11678 - 81
17TYRTYRASNASN(chain 'A' and (resid 60 or resid 62 through 63...AA119 - 12184 - 86
18GLUGLUTHRTHR(chain 'A' and (resid 60 or resid 62 through 63...AA124 - 16689 - 131
21THRTHRTHRTHR(chain 'B' and (resid 60 or resid 62 through 63...BB6025
22GLNGLNLEULEU(chain 'B' and (resid 60 or resid 62 through 63...BB62 - 6327 - 28
23TYRTYRLEULEU(chain 'B' and (resid 60 or resid 62 through 63...BB65 - 6730 - 32
24VALVALTRPTRP(chain 'B' and (resid 60 or resid 62 through 63...BB69 - 7534 - 40
25HISHISLYSLYS(chain 'B' and (resid 60 or resid 62 through 63...BB77 - 11142 - 76
26ARGARGASNASN(chain 'B' and (resid 60 or resid 62 through 63...BB113 - 11678 - 81
27TYRTYRASNASN(chain 'B' and (resid 60 or resid 62 through 63...BB119 - 12184 - 86
28GLUGLUTHRTHR(chain 'B' and (resid 60 or resid 62 through 63...BB124 - 16689 - 131

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Components

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


Mass: 17200.648 Da / Num. of mol.: 2
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: Protein/peptide cyclic peptide 3.2_1


Mass: 2075.625 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical ChemComp-NH2 / AMINO GROUP


Mass: 16.023 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: NH2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 214 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.21 Å3/Da / Density % sol: 61.63 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 2% v/v 1,4-Dioxane, 0.1 M Tris pH 8.0, 15% w/v Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 23, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.95→47.08 Å / Num. obs: 28961 / % possible obs: 100 % / Redundancy: 13 % / Biso Wilson estimate: 34.76 Å2 / CC1/2: 0.999 / Net I/σ(I): 22.1
Reflection shellResolution: 1.95→2 Å / Num. unique obs: 2011 / CC1/2: 0.965

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LYI

4lyi


Resolution: 1.95→37.02 Å / SU ML: 0.129 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 20.3317
RfactorNum. reflection% reflection
Rfree0.1999 1493 5.17 %
Rwork0.17 --
obs0.1716 28898 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 41.24 Å2
Refinement stepCycle: LAST / Resolution: 1.95→37.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2120 0 1 214 2335
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00762179
X-RAY DIFFRACTIONf_angle_d0.91182956
X-RAY DIFFRACTIONf_chiral_restr0.0541320
X-RAY DIFFRACTIONf_plane_restr0.0053374
X-RAY DIFFRACTIONf_dihedral_angle_d10.85361326
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-2.010.22841450.18472438X-RAY DIFFRACTION100
2.01-2.080.22061250.18172454X-RAY DIFFRACTION100
2.08-2.170.22921320.17512453X-RAY DIFFRACTION99.92
2.17-2.270.22621440.17352445X-RAY DIFFRACTION100
2.27-2.390.20781370.17822477X-RAY DIFFRACTION100
2.39-2.540.21181250.17852461X-RAY DIFFRACTION99.96
2.54-2.730.24361310.18872491X-RAY DIFFRACTION100
2.73-3.010.22321310.19022485X-RAY DIFFRACTION100
3.01-3.440.2471480.19032521X-RAY DIFFRACTION100
3.44-4.330.15771260.15422537X-RAY DIFFRACTION100
4.33-37.020.17391490.15272643X-RAY DIFFRACTION99.86
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)
10.01581659281240.01053336316560.0103938176730.298282505430.1251521321020.231473622198-0.5057713818780.0667582152009-0.75853870605-0.1360554654780.7231221817220.492674941349-0.342486853515-0.08527680649930.004568247183850.361980819571-0.0350454283210.006283377617350.766564217841-0.00314878293420.4782438870424.94662538209-15.624665347714.3214298612
20.03370033455970.00575600130868-0.02728032747140.03076723146810.007110390685050.0653892889279-0.118990583571-0.3422711457810.2420526361130.364392143692-0.253039471346-0.8333121489920.580567965790.3182362502590.00160833592430.351071104663-0.00457251971528-0.003447839024430.699693007663-0.007693970465080.433575123781-3.23824500821-16.977810896125.8494226641
30.0600963137313-0.02226817456810.08533201759120.05391295088510.04066963492240.1390338920590.1760034972860.470106390501-0.267013263578-0.1253603218750.0442219468972-0.3611176858490.3717449355550.6344541078670.005163593455940.2916311832860.00914959595377-0.02583046444970.536849948949-0.02008848195110.421400257268-11.7043287461-16.547166056837.5541065608
40.1071534003530.276729501475-0.2390934661590.531679163553-0.4828177009450.3984231479-0.09220300360060.3162611650160.008994656800880.108411589524-0.186886837084-0.1890483295810.492288697838-0.644972346768-0.0006711458429410.317306418995-0.007545741136260.07109267866980.3835313825130.008446312716840.316517916807-21.3800006654-23.566904589624.0525521733
50.267686541499-0.0854922093314-0.3472623552760.2503427754820.4812600639241.30976371863-0.285192022239-0.186123516826-0.429478665041-0.483246953709-0.00951824902295-0.4260541277990.2541781531290.37190831555-0.01234754526970.3676699558590.03422141626090.0727939206910.327858687072-0.01691501416850.348230152398-7.00977716944-20.77615894918.59789341995
60.6451373553380.00665746496746-0.5228816399680.5338313206060.4169160297010.7999708753370.0119520114141-0.360675027323-0.0560019036690.155801766166-0.146006548809-0.2015346722480.0337932698950.5269465416621.16948675052E-60.2967385832670.0281869185436-0.02531512030630.3606300083980.001892218861910.324126634315-8.66245627964-15.28357968522.2226939814
70.7150439825560.190162406570.07904626554930.486453992883-0.4798678456710.4472220332310.180918808197-0.1290690136870.1405189730980.074666613874-0.1344347269140.0918547207084-0.540227933652-0.195683335997-7.89621055745E-50.3217973261110.02491514025870.002367684333050.300243745239-0.009923139985460.329458041083-14.6616729949-11.625386497516.7646717969
80.006586521956670.0222826635444-0.01514210338580.0474596678639-0.01658479384240.0715495447842-0.2123319944670.274404383668-0.35736649795-0.9275104643470.1203649555260.1790078144690.1640851121680.40815603973-0.000937362532440.4019020815080.0361504948012-0.07440290578340.372091800783-0.03267167598620.40748475571-12.9098623012-11.60410562310.247969863921
90.29749827473-0.5646573702960.1792985297491.31981799097-1.059334987180.96975683431-0.02044611276530.2025937121120.0582541790596-0.2790922212340.2152281279330.4210467924990.1255363722-0.7297794133980.006961272667320.2716321157490.0111708227516-0.03246187132510.38867969439-0.02222159341830.378391300476-23.6529801397-17.019089439514.2100885353
100.2299787419550.1042546925850.07815389577810.1954352148030.2166346341210.5891680399530.08514088412690.1215348106110.3576880123740.13095989271-0.387827338957-0.859431753119-0.2715105368940.28926534648-0.05462642682880.3488685932910.0363667867557-0.06703853405440.2721074768570.05091342932310.443301336467-11.40276159270.01323369451485.10944608674
110.748048586816-0.194755924843-0.4333780688070.8396877893380.7408791583330.6771917429390.1079872749080.236205740029-0.224573244254-0.223839127248-0.1861211301950.226021570130.257000603289-0.00762138841684-0.03836482930860.3124923407950.00538522691786-0.07993894462860.248550143236-0.007100518041970.332013602646-33.3016404776-0.9036215473460.291452962288
120.2238472715130.1884757369370.1888619289460.151487673090.1647971413960.1005990852960.1212077739050.239337464420.404135693889-0.249748095003-0.114041468133-0.148475307344-0.05387793682420.128784366398.51790186806E-50.3452205010980.0359475325656-0.01022993737280.2908738638080.04187836575710.330210553388-35.404937048912.3201885013-1.85191207671
130.4226533880280.0944582977645-0.3818969106960.248846837662-0.1572838487880.470336277130.07891419781220.272785794405-0.0903516533944-0.424085358631-0.0203651116634-0.357383430559-0.004178727169620.200579053658-4.36812978552E-50.3434530490.03884969325440.04489230198330.3109239459950.01542476727590.298012114467-18.37244832554.8011960528-2.57091559746
140.25156362269-0.22010080846-0.3417162063630.870002709684-0.367236737411.07033884659-0.0126742363591-0.1687945660010.470220283966-0.0295540362504-0.0432207483253-0.0117043928353-0.107383095918-0.0219184907137-9.12860299084E-50.3190569900040.01170948191220.001144590327940.275302095278-0.006787366167030.289986768305-28.59941565538.840180611865.87537783099
151.02398147801-0.764153056599-0.4906326964730.886317960714-0.1185783032160.893758371649-0.126021589368-0.593466522334-0.07115882500180.4086608513080.1380367148560.186923621940.0600475585397-0.0990619700945-0.03255176721010.369133852368-0.0215931256504-0.02815051408940.3404755754070.00551369111570.241790900093-28.89431161041.6610004750312.4045863308
160.0640577232160.03850508657430.1045397539240.07326672866850.06601768876610.09995397168570.1942705972170.10086767035-0.4003081336030.483534395478-0.1811526912480.9068860463090.353716255657-0.0859732505261-0.0001191436312270.403999451439-0.0301190945413-0.060854992710.301312304449-0.042448045460.499674527607-41.0776232011-6.16409454583-2.26402072952
171.14548074033-1.71304524758-1.542815686832.750543826132.256725901162.03161088014-0.112771335538-0.167083355299-0.04311111939431.06836953832-0.3146729828360.5400382695150.495821486092-0.403040071517-0.2670577665710.327219197841-0.0200976513534-0.09978419391690.331104844418-0.05707477817230.468917316492-41.6373691812-8.5872013018-0.0354587238985
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 42 through 46 )
2X-RAY DIFFRACTION2chain 'A' and (resid 47 through 51 )
3X-RAY DIFFRACTION3chain 'A' and (resid 52 through 60 )
4X-RAY DIFFRACTION4chain 'A' and (resid 61 through 76 )
5X-RAY DIFFRACTION5chain 'A' and (resid 77 through 96 )
6X-RAY DIFFRACTION6chain 'A' and (resid 97 through 121 )
7X-RAY DIFFRACTION7chain 'A' and (resid 122 through 139 )
8X-RAY DIFFRACTION8chain 'A' and (resid 140 through 144 )
9X-RAY DIFFRACTION9chain 'A' and (resid 145 through 166 )
10X-RAY DIFFRACTION10chain 'B' and (resid 58 through 68 )
11X-RAY DIFFRACTION11chain 'B' and (resid 69 through 96 )
12X-RAY DIFFRACTION12chain 'B' and (resid 97 through 106 )
13X-RAY DIFFRACTION13chain 'B' and (resid 107 through 121 )
14X-RAY DIFFRACTION14chain 'B' and (resid 122 through 139 )
15X-RAY DIFFRACTION15chain 'B' and (resid 140 through 167 )
16X-RAY DIFFRACTION16chain 'C' and (resid 1 through 6 )
17X-RAY DIFFRACTION17chain 'C' and (resid 7 through 17 )

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Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

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