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- PDB-4a9k: BROMODOMAIN OF HUMAN CREBBP WITH N-(4-hydroxyphenyl)acetamide -

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Basic information

Entry
Database: PDB / ID: 4a9k
TitleBROMODOMAIN OF HUMAN CREBBP WITH N-(4-hydroxyphenyl)acetamide
ComponentsCREB-BINDING PROTEIN
KeywordsSIGNALING PROTEIN / INHIBITOR / HISTONE / EPIGENETIC READER
Function / homology
Function and homology information


peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / peptide N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / histone H3K18 acetyltransferase activity / regulation of smoothened signaling pathway / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production ...peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / peptide N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / histone H3K18 acetyltransferase activity / regulation of smoothened signaling pathway / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / NFE2L2 regulating MDR associated enzymes / MRF binding / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Regulation of FOXO transcriptional activity by acetylation / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / RUNX3 regulates NOTCH signaling / Regulation of gene expression by Hypoxia-inducible Factor / Nuclear events mediated by NFE2L2 / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of NFE2L2 gene expression / negative regulation of transcription by RNA polymerase I / NOTCH3 Intracellular Domain Regulates Transcription / TRAF6 mediated IRF7 activation / FOXO-mediated transcription of cell death genes / peptide-lysine-N-acetyltransferase activity / NFE2L2 regulating tumorigenic genes / NFE2L2 regulating anti-oxidant/detoxification enzymes / embryonic digit morphogenesis / homeostatic process / protein acetylation / Notch-HLH transcription pathway / positive regulation of transforming growth factor beta receptor signaling pathway / Formation of paraxial mesoderm / stimulatory C-type lectin receptor signaling pathway / acetyltransferase activity / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / histone acetyltransferase complex / Attenuation phase / positive regulation of double-strand break repair via homologous recombination / cellular response to nutrient levels / Transcriptional and post-translational regulation of MITF-M expression and activity / canonical NF-kappaB signal transduction / histone acetyltransferase activity / regulation of cellular response to heat / histone acetyltransferase / RORA activates gene expression / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / Regulation of lipid metabolism by PPARalpha / NPAS4 regulates expression of target genes / CD209 (DC-SIGN) signaling / BMAL1:CLOCK,NPAS2 activates circadian gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / Formation of the beta-catenin:TCF transactivating complex / Heme signaling / protein destabilization / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / chromatin DNA binding / Evasion by RSV of host interferon responses / NOTCH1 Intracellular Domain Regulates Transcription / transcription coactivator binding / Pre-NOTCH Transcription and Translation / Transcriptional regulation of white adipocyte differentiation / positive regulation of protein localization to nucleus / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Activation of anterior HOX genes in hindbrain development during early embryogenesis / transcription corepressor activity / cellular response to UV / p53 binding / Circadian Clock / rhythmic process / TRAF3-dependent IRF activation pathway / HATs acetylate histones / protein-containing complex assembly / DNA-binding transcription factor binding / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / transcription regulator complex / damaged DNA binding / transcription coactivator activity / response to hypoxia / nuclear body / chromatin binding / regulation of DNA-templated transcription / chromatin / SARS-CoV-2 activates/modulates innate and adaptive immune responses / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Nuclear receptor coactivator, CREB-bp-like, interlocking / Nuclear receptor coactivator, CREB-bp-like, interlocking domain superfamily / Creb binding / Zinc finger, TAZ-type / TAZ domain superfamily / TAZ zinc finger / Zinc finger TAZ-type profile. / TAZ zinc finger, present in p300 and CBP / Coactivator CBP, KIX domain / CREB-binding protein/p300, atypical RING domain ...Nuclear receptor coactivator, CREB-bp-like, interlocking / Nuclear receptor coactivator, CREB-bp-like, interlocking domain superfamily / Creb binding / Zinc finger, TAZ-type / TAZ domain superfamily / TAZ zinc finger / Zinc finger TAZ-type profile. / TAZ zinc finger, present in p300 and CBP / Coactivator CBP, KIX domain / CREB-binding protein/p300, atypical RING domain / CBP/p300-type histone acetyltransferase domain / CBP/p300, atypical RING domain superfamily / KIX domain / CREB-binding protein/p300, atypical RING domain / KIX domain profile. / CBP/p300-type histone acetyltransferase (HAT) domain profile. / Histone acetyltransferase Rtt109/CBP / Histone acetylation protein / Histone acetylation protein / Coactivator CBP, KIX domain superfamily / Zinc finger ZZ-type signature. / Zinc-binding domain, present in Dystrophin, CREB-binding protein. / Zinc finger, ZZ type / Zinc finger, ZZ-type / Zinc finger, ZZ-type superfamily / Zinc finger ZZ-type profile. / Nuclear receptor coactivator, interlocking / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
: / THIOCYANATE ION / N-(4-HYDROXYPHENYL)ACETAMIDE (TYLENOL) / CREB-binding protein
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.81 Å
AuthorsChung, C.W. / Bamborough, P.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Fragment-Based Discovery of Bromodomain Inhibitors Part 1: Inhibitor Binding Modes and Implications for Lead Discovery.
Authors: Chung, C.W. / Dean, A.W. / Woolven, J.M. / Bamborough, P.
History
DepositionNov 26, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 11, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2012Group: Other
Revision 1.2Apr 3, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CREB-BINDING PROTEIN
B: CREB-BINDING PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,9708
Polymers28,4472
Non-polymers5246
Water4,810267
1
A: CREB-BINDING PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,5575
Polymers14,2231
Non-polymers3334
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CREB-BINDING PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4143
Polymers14,2231
Non-polymers1902
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)120.943, 120.943, 40.471
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein CREB-BINDING PROTEIN / HUMAN CREBBP


Mass: 14223.349 Da / Num. of mol.: 2 / Fragment: BROMODOMAIN, RESIDUES 1081-1197
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: Q92793, histone acetyltransferase

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Non-polymers , 5 types, 273 molecules

#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-TYL / N-(4-HYDROXYPHENYL)ACETAMIDE (TYLENOL)


Mass: 151.163 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H9NO2 / Comment: medication*YM
#4: Chemical ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CNS
#5: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 267 / 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: 2 Å3/Da / Density % sol: 38.58 % / Description: NONE
Crystal growTemperature: 277 K / Details: 150 MM KSCN, 20% PEG 3350, 4 DEGREES CELSIUS.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54178
DetectorType: RIGAKU SATURN A200 / Detector: CCD / Date: Jun 26, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.81→40 Å / Num. obs: 19824 / % possible obs: 98.2 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 14.5
Reflection shellResolution: 1.81→1.84 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.43 / Mean I/σ(I) obs: 3.3 / % possible all: 99.2

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
HKLdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.81→60.47 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.943 / SU B: 5.586 / SU ML: 0.081 / Cross valid method: THROUGHOUT / ESU R: 0.138 / ESU R Free: 0.124 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.19748 826 4.2 %RANDOM
Rwork0.16025 ---
obs0.16175 18998 97.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 32.005 Å2
Baniso -1Baniso -2Baniso -3
1--0.88 Å2-0.44 Å20 Å2
2---0.88 Å20 Å2
3---1.32 Å2
Refinement stepCycle: LAST / Resolution: 1.81→60.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1888 0 34 267 2189
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0221997
X-RAY DIFFRACTIONr_bond_other_d0.0010.021402
X-RAY DIFFRACTIONr_angle_refined_deg0.9991.9852710
X-RAY DIFFRACTIONr_angle_other_deg0.82933403
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7845227
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.77224.369103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.3315341
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4521514
X-RAY DIFFRACTIONr_chiral_restr0.0540.2282
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212178
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02414
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_it0.57121160
X-RAY DIFFRACTIONr_mcbond_other0.0682440
X-RAY DIFFRACTIONr_mcangle_it1.11741895
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.3074837
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.1986814
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.806→1.853 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.188 50 -
Rwork0.202 1363 -
obs--93.58 %
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)
10.4908-0.08670.15981.56690.32140.82880.01360.0251-0.075-0.0294-0.01510.14730.0566-0.00940.00150.0236-0.00430.00170.0170.00240.0439-24.358217.0214-5.8507
21.29590.09820.30932.0572-0.01151.4945-0.0545-0.03290.0601-0.0127-0.01390.0484-0.10520.08630.06840.0595-0.0077-0.01220.0110.00460.0081-14.4805-7.5301-1.6754
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1083 - 1197
2X-RAY DIFFRACTION2B1085 - 1196

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