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- PDB-6mnl: NMR solution structures of second bromodomain of BRD4 with FOXO3a... -

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Basic information

Entry
Database: PDB / ID: 6mnl
TitleNMR solution structures of second bromodomain of BRD4 with FOXO3a peptide
Components
  • Bromodomain-containing protein 4
  • FOXO3a peptide
KeywordsTRANSCRIPTION / BRD4 / CDK6 / AKT / luminal breast cancer
Function / homology
Function and homology information


positive regulation of muscle atrophy / initiation of primordial ovarian follicle growth / positive regulation of hydrogen peroxide-mediated programmed cell death / RNA polymerase II transcription repressor complex / mitochondrial transcription factor activity / RUNX3 regulates BCL2L11 (BIM) transcription / cellular response to corticosterone stimulus / FOXO-mediated transcription of cell cycle genes / AKT phosphorylates targets in the nucleus / ovulation from ovarian follicle ...positive regulation of muscle atrophy / initiation of primordial ovarian follicle growth / positive regulation of hydrogen peroxide-mediated programmed cell death / RNA polymerase II transcription repressor complex / mitochondrial transcription factor activity / RUNX3 regulates BCL2L11 (BIM) transcription / cellular response to corticosterone stimulus / FOXO-mediated transcription of cell cycle genes / AKT phosphorylates targets in the nucleus / ovulation from ovarian follicle / response to water-immersion restraint stress / mitochondrial transcription / neuronal stem cell population maintenance / regulation of neural precursor cell proliferation / response to fatty acid / positive regulation of endothelial cell apoptotic process / positive regulation of regulatory T cell differentiation / Signaling by NODAL / brain morphogenesis / oocyte maturation / Regulation of FOXO transcriptional activity by acetylation / positive regulation of reactive oxygen species biosynthetic process / FOXO-mediated transcription of cell death genes / antral ovarian follicle growth / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / response to dexamethasone / response to starvation / Constitutive Signaling by AKT1 E17K in Cancer / RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / Regulation of localization of FOXO transcription factors / P-TEFb complex binding / DNA damage response, signal transduction by p53 class mediator / negative regulation of neuron differentiation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / negative regulation by host of viral transcription / canonical Wnt signaling pathway / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / cellular response to glucose starvation / positive regulation of autophagy / positive regulation of T-helper 17 cell lineage commitment / extrinsic apoptotic signaling pathway in absence of ligand / tumor necrosis factor-mediated signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / FLT3 Signaling / RNA polymerase II CTD heptapeptide repeat kinase activity / negative regulation of cell migration / cellular response to nerve growth factor stimulus / positive regulation of erythrocyte differentiation / condensed nuclear chromosome / transcription coregulator binding / cellular response to glucose stimulus / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / MAPK6/MAPK4 signaling / lysine-acetylated histone binding / negative regulation of canonical Wnt signaling pathway / chromatin DNA binding / beta-catenin binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / positive regulation of miRNA transcription / cellular response to amyloid-beta / sequence-specific double-stranded DNA binding / positive regulation of neuron apoptotic process / p53 binding / regulation of translation / chromosome / cellular response to oxidative stress / regulation of inflammatory response / cellular response to hypoxia / DNA-binding transcription activator activity, RNA polymerase II-specific / Interleukin-4 and Interleukin-13 signaling / positive regulation of canonical NF-kappaB signal transduction / mitochondrial outer membrane / sequence-specific DNA binding / Potential therapeutics for SARS / transcription coactivator activity / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / mitochondrial matrix / chromatin remodeling / response to xenobiotic stimulus / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / DNA damage response / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
FOXO protein, KIX-binding domain / KIX-binding domain of forkhead box O, CR2 / FOXO protein, transactivation domain / Transactivation domain of FOXO protein family / Fork head domain / Forkhead domain / Fork head domain profile. / FORKHEAD / Fork head domain conserved site 2 / Fork head domain signature 2. ...FOXO protein, KIX-binding domain / KIX-binding domain of forkhead box O, CR2 / FOXO protein, transactivation domain / Transactivation domain of FOXO protein family / Fork head domain / Forkhead domain / Fork head domain profile. / FORKHEAD / Fork head domain conserved site 2 / Fork head domain signature 2. / 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 / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Forkhead box protein O3 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / torsion angle dynamics / simulated annealing
AuthorsZeng, L. / Zhou, M.-M.
CitationJournal: Nat Commun / Year: 2018
Title: Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer.
Authors: Liu, J. / Duan, Z. / Guo, W. / Zeng, L. / Wu, Y. / Chen, Y. / Tai, F. / Wang, Y. / Lin, Y. / Zhang, Q. / He, Y. / Deng, J. / Stewart, R.L. / Wang, C. / Lin, P.C. / Ghaffari, S. / Evers, B.M. ...Authors: Liu, J. / Duan, Z. / Guo, W. / Zeng, L. / Wu, Y. / Chen, Y. / Tai, F. / Wang, Y. / Lin, Y. / Zhang, Q. / He, Y. / Deng, J. / Stewart, R.L. / Wang, C. / Lin, P.C. / Ghaffari, S. / Evers, B.M. / Liu, S. / Zhou, M.M. / Zhou, B.P. / Shi, J.
History
DepositionOct 2, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 19, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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 1.2Jun 14, 2023Group: Data collection / Database references / Other
Category: database_2 / pdbx_database_status ...database_2 / pdbx_database_status / pdbx_nmr_software / pdbx_nmr_spectrometer
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_nmr_data / _pdbx_nmr_software.name / _pdbx_nmr_spectrometer.model
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Category: atom_site / chem_comp_atom / chem_comp_bond / Item: _atom_site.auth_atom_id / _atom_site.label_atom_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: FOXO3a peptide
B: Bromodomain-containing protein 4


Theoretical massNumber of molelcules
Total (without water)16,5952
Polymers16,5952
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area1240 Å2
ΔGint-9 kcal/mol
Surface area9380 Å2
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)20 / 200structures with the lowest energy
RepresentativeModel #1lowest energy

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Components

#1: Protein/peptide FOXO3a peptide


Mass: 1752.954 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: O43524*PLUS
#2: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 14842.058 Da / Num. of mol.: 1 / Fragment: Bromo 2 domain, residues 333-460
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

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic12D 1H-15N HSQC
121isotropic13D HN(CA)CB
131isotropic13D CBCA(CO)NH
141isotropic33D 1H-15N NOESY
152isotropic13D 1H-13C NOESY aliphatic
162isotropic13D 1H-13C NOESY aromatic
182isotropic13D filtered 1H-13C NOESY aliphatic
172isotropic23D filtered 1H-13C NOESY aromatic

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Sample preparation

Details
TypeSolution-IDContentsLabelSolvent system
solution1100 mM sodium chloride, 10 mM sodium phosphate, 2 mM [U-100% 2H] DTT, 95% H2O/5% D2OH2O_sample95% H2O/5% D2O
solution2100 mM sodium chloride, 10 mM sodium phosphate, 2 mM [U-100% 2H] DTT, 100% D2OD2O_sample100% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
100 mMsodium chloridenatural abundance1
10 mMsodium phosphatenatural abundance1
2 mMDTT[U-100% 2H]1
100 mMsodium chloridenatural abundance2
10 mMsodium phosphatenatural abundance2
2 mMDTT[U-100% 2H]2
Sample conditionsIonic strength units: Not defined / Label: condition_1 / pH: 6.5 / Pressure: 1 atm / Temperature: 298 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AVANCEBrukerAVANCE8001
Bruker AVANCEBrukerAVANCE5002
Bruker AVANCEBrukerAVANCE7003

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Processing

NMR software
NameVersionDeveloperClassification
ARIA2.3Linge, O'Donoghue and Nilgesrefinement
CNSBrunger, Adams, Clore, Gros, Nilges and Readrefinement
NMRView5Johnson, One Moon Scientificchemical shift assignment
NMRView5Johnson, One Moon Scientificpeak picking
ProcheckNMRLaskowski and MacArthurdata analysis
NMRPipeDelaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
TopSpinBruker Biospincollection
CNSBrunger, Adams, Clore, Gros, Nilges and Readstructure calculation
Refinement
MethodSoftware ordinal
torsion angle dynamics2
simulated annealing1
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 200 / Conformers submitted total number: 20

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