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- PDB-6ay3: CREBBP bromodomain in complex with Cpd16 (5-(7-(difluoromethyl)-6... -

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Basic information

Entry
Database: PDB / ID: 6ay3
TitleCREBBP bromodomain in complex with Cpd16 (5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1H-indole-3-carboxamide)
ComponentsCREB-binding protein
KeywordsTRANSFERASE/TRANSFERASE inhibitor / CREBBP / Bromodomain / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


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 / regulation of smoothened signaling pathway / histone H3K18 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / NFE2L2 regulates pentose phosphate pathway genes ...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 / regulation of smoothened signaling pathway / histone H3K18 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / NFE2L2 regulates pentose phosphate pathway genes / MRF binding / NFE2L2 regulating MDR associated enzymes / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / RUNX3 regulates NOTCH signaling / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of FOXO transcriptional activity by acetylation / Regulation of gene expression by Hypoxia-inducible Factor / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / negative regulation of transcription by RNA polymerase I / NOTCH3 Intracellular Domain Regulates Transcription / NFE2L2 regulating anti-oxidant/detoxification enzymes / TRAF6 mediated IRF7 activation / peptide-lysine-N-acetyltransferase activity / FOXO-mediated transcription of cell death genes / NFE2L2 regulating tumorigenic genes / embryonic digit morphogenesis / homeostatic process / Notch-HLH transcription pathway / protein acetylation / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / non-canonical NF-kappaB signal transduction / Zygotic genome activation (ZGA) / stimulatory C-type lectin receptor signaling pathway / acetyltransferase activity / cellular response to nutrient levels / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / histone acetyltransferase complex / Attenuation phase / regulation of cellular response to heat / histone acetyltransferase activity / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / histone acetyltransferase / RORA activates gene expression / NPAS4 regulates expression of target genes / Regulation of lipid metabolism by PPARalpha / 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 / protein destabilization / Heme signaling / Transcriptional activation of mitochondrial biogenesis / transcription coactivator binding / PPARA activates gene expression / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / chromatin DNA binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Pre-NOTCH Transcription and Translation / Transcriptional regulation of white adipocyte differentiation / Activation of anterior HOX genes in hindbrain development during early embryogenesis / positive regulation of protein localization to nucleus / transcription corepressor activity / cellular response to UV / rhythmic process / Circadian Clock / p53 binding / TRAF3-dependent IRF activation pathway / HATs acetylate histones / protein-containing complex assembly / DNA-binding transcription factor binding / Estrogen-dependent gene expression / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / damaged DNA binding / transcription coactivator activity / response to hypoxia / nuclear body / chromatin binding / chromatin / regulation of DNA-templated transcription / 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. / Coactivator CBP, KIX domain superfamily / Histone acetyltransferase Rtt109/CBP / Histone acetylation protein / Histone acetylation protein / 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
Chem-C3J / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.391 Å
AuthorsMurray, J.M.
CitationJournal: J. Med. Chem. / Year: 2017
Title: A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors.
Authors: Bronner, S.M. / Murray, J. / Romero, F.A. / Lai, K.W. / Tsui, V. / Cyr, P. / Beresini, M.H. / de Leon Boenig, G. / Chen, Z. / Choo, E.F. / Clark, K.R. / Crawford, T.D. / Jayaram, H. / ...Authors: Bronner, S.M. / Murray, J. / Romero, F.A. / Lai, K.W. / Tsui, V. / Cyr, P. / Beresini, M.H. / de Leon Boenig, G. / Chen, Z. / Choo, E.F. / Clark, K.R. / Crawford, T.D. / Jayaram, H. / Kaufman, S. / Li, R. / Li, Y. / Liao, J. / Liang, X. / Liu, W. / Ly, J. / Maher, J. / Wai, J. / Wang, F. / Zheng, A. / Zhu, X. / Magnuson, S.
History
DepositionSep 7, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 21, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 4, 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
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: CREB-binding protein
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,4557
Polymers27,4372
Non-polymers1,0185
Water5,927329
1
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,2394
Polymers13,7191
Non-polymers5213
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,2163
Polymers13,7191
Non-polymers4982
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)33.910, 80.448, 48.522
Angle α, β, γ (deg.)90.000, 109.060, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein CREB-binding protein /


Mass: 13718.702 Da / Num. of mol.: 2 / Fragment: Bromodomain (UNP residue 1083-1197)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP, CBP / Production host: Escherichia coli (E. coli) / References: UniProt: Q92793, histone acetyltransferase
#2: Chemical ChemComp-C3J / 5-[7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl]-N-methyl-1H-indole-3-carboxamide


Mass: 435.469 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23F2N5O
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 329 / Source method: isolated from a natural source / Formula: H2O

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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: 2.28 Å3/Da / Density % sol: 46.05 % / Mosaicity: 0.578 °
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 6.5 / Details: 0.2M MgCl2, 0.1M Bis-Tris pH6.5, 22% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 1.39→50 Å / Num. obs: 49193 / % possible obs: 99.8 % / Redundancy: 3.7 % / Biso Wilson estimate: 12.16 Å2 / Rmerge(I) obs: 0.084 / Rpim(I) all: 0.051 / Rrim(I) all: 0.099 / Χ2: 1.116 / Net I/σ(I): 8 / Num. measured all: 181476
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.39-1.443.60.67748890.6530.4170.7981.17899.9
1.44-1.53.60.48649200.7990.2990.5721.205100
1.5-1.573.70.3548900.880.2140.4111.16699.9
1.57-1.653.70.2749250.9240.1660.3181.16699.9
1.65-1.753.70.19848910.9580.1210.2331.13899.8
1.75-1.893.70.14549460.9730.0880.171.09599.9
1.89-2.083.70.1148990.9840.0660.1281.05899.8
2.08-2.383.70.09149100.9850.0550.1071.08199.8
2.38-2.993.70.06649260.9920.040.0771.06799.6
2.99-503.80.0549970.9950.030.0581.01599.4

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXdev_2747refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdbid 5I8B

5i8b


Resolution: 1.391→29.775 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.91
RfactorNum. reflection% reflection
Rfree0.2372 2507 5.1 %
Rwork0.2017 --
obs0.2036 49156 99.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 65.35 Å2 / Biso mean: 18.1426 Å2 / Biso min: 6.75 Å2
Refinement stepCycle: final / Resolution: 1.391→29.775 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1932 0 73 329 2334
Biso mean--14.56 27.74 -
Num. residues----230
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0142200
X-RAY DIFFRACTIONf_angle_d1.4213004
X-RAY DIFFRACTIONf_chiral_restr0.103296
X-RAY DIFFRACTIONf_plane_restr0.01395
X-RAY DIFFRACTIONf_dihedral_angle_d21.189839
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 18

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.3908-1.41750.3911380.32012533267197
1.4175-1.44640.28291320.292925732705100
1.4464-1.47790.28641410.26725992740100
1.4779-1.51230.28751460.241725612707100
1.5123-1.55010.27221440.240325812725100
1.5501-1.5920.29671130.220126282741100
1.592-1.63880.26381380.210125952733100
1.6388-1.69170.29031410.212325872728100
1.6917-1.75220.23411440.205225872731100
1.7522-1.82230.25041560.197825732729100
1.8223-1.90530.241540.199425862740100
1.9053-2.00570.23091330.204226042737100
2.0057-2.13130.23971420.198625992741100
2.1313-2.29580.24841480.196925862734100
2.2958-2.52670.22211160.20062591270799
2.5267-2.89210.23131370.202326252762100
2.8921-3.64270.21511380.178926162754100
3.6427-29.7820.1971460.17632625277199
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)
10.65250.0950.02991.1252-0.32450.5761-0.0006-0.0167-0.02230.01780.01880.08270.0092-0.02550.00260.070.00170.00920.08570.01610.095.035-6.83719.677
20.8713-0.33790.13071.1086-0.18450.86420.0440.08860.0205-0.1402-0.0439-0.01-0.0308-0.00090.00490.10010.005-0.00170.09510.00230.07721.9876.5130.896
32.04630.82890.07970.7438-0.05590.0222-0.0008-0.0810.00340.11560.002-0.0201-0.01410.022-0.07410.1482-0.00610.01830.1456-0.01210.086833.396-2.0221.318
41.2734-0.91040.10751.3199-0.23910.04840.03040.11420.0069-0.121-0.0975-0.06750.04490.0852-0.16830.12180.0093-0.0010.130.01090.064416.5851.67119.748
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 1083:1197 )A1083 - 1197
2X-RAY DIFFRACTION2( CHAIN B AND RESID 1083:1197 )B1083 - 1197
3X-RAY DIFFRACTION3( CHAIN B AND RESID 1201:1201 )B1201
4X-RAY DIFFRACTION4( CHAIN A AND RESID 1201:1201 )A1201

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