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- PDB-5w0l: CREBBP Bromodomain in complex with Cpd10 (1-(3-(7-(difluoromethyl... -

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Basic information

Entry
Database: PDB / ID: 5w0l
TitleCREBBP Bromodomain in complex with Cpd10 (1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one)
ComponentsCREB-binding protein
KeywordsTRANSCRIPTION REGULATOR/INHIBITOR / CREBBP / Bromodomain / small molecule inhibitor / TRANSCRIPTION REGULATOR-INHIBITOR complex
Function / homology
Function and homology information


peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / protein N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / histone lactyltransferase (CoA-dependent) activity / N-terminal peptidyl-lysine acetylation / regulation of smoothened signaling pathway / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes ...peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / protein N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / histone lactyltransferase (CoA-dependent) activity / N-terminal peptidyl-lysine acetylation / regulation of smoothened signaling pathway / 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 / Nuclear events mediated by NFE2L2 / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of NFE2L2 gene expression / Regulation of gene expression by Hypoxia-inducible Factor / negative regulation of transcription by RNA polymerase I / NOTCH3 Intracellular Domain Regulates Transcription / TRAF6 mediated IRF7 activation / NFE2L2 regulating tumorigenic genes / NFE2L2 regulating anti-oxidant/detoxification enzymes / protein-lysine-acetyltransferase activity / embryonic digit morphogenesis / protein acetylation / homeostatic process / Notch-HLH transcription pathway / histone acetyltransferase activity / positive regulation of transforming growth factor beta receptor signaling pathway / Formation of paraxial mesoderm / acetyltransferase activity / FOXO-mediated transcription of cell death genes / stimulatory C-type lectin receptor signaling pathway / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / histone acetyltransferase complex / canonical NF-kappaB signal transduction / 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 / Attenuation phase / histone H4K16 acetyltransferase activity / histone H3K56 acetyltransferase activity / histone H3K23 acetyltransferase activity / histone H2AK5 acetyltransferase activity / histone H2AK9 acetyltransferase activity / histone H2BK5 acetyltransferase activity / histone H2BK12 acetyltransferase activity / histone H3K4 acetyltransferase activity / histone H3K27 acetyltransferase activity / histone H3K36 acetyltransferase activity / histone H3K122 acetyltransferase activity / regulation of cellular response to heat / histone H3K18 acetyltransferase activity / histone H3K9 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H4K12 acetyltransferase activity / histone acetyltransferase / : / Regulation of lipid metabolism by PPARalpha / NPAS4 regulates expression of target genes / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / CD209 (DC-SIGN) signaling / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / transcription coactivator binding / Heme signaling / Formation of the beta-catenin:TCF transactivating complex / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / protein destabilization / Evasion by RSV of host interferon responses / chromatin DNA binding / Transcriptional regulation of white adipocyte differentiation / NOTCH1 Intracellular Domain Regulates Transcription / Pre-NOTCH Transcription and Translation / 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 / : / rhythmic process / HATs acetylate histones / TRAF3-dependent IRF activation pathway / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / protein-containing complex assembly / DNA-binding transcription factor binding / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / Estrogen-dependent gene expression
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
Chem-9UD / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.549 Å
AuthorsMurray, J.M.
CitationJournal: J. Med. Chem. / Year: 2017
Title: GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP).
Authors: Romero, F.A. / Murray, J. / Lai, K.W. / Tsui, V. / Albrecht, B.K. / An, L. / Beresini, M.H. / de Leon Boenig, G. / Bronner, S.M. / Chan, E.W. / Chen, K.X. / Chen, Z. / Choo, E.F. / Clagg, K. ...Authors: Romero, F.A. / Murray, J. / Lai, K.W. / Tsui, V. / Albrecht, B.K. / An, L. / Beresini, M.H. / de Leon Boenig, G. / Bronner, S.M. / Chan, E.W. / Chen, K.X. / Chen, Z. / Choo, E.F. / Clagg, K. / Clark, K. / Crawford, T.D. / Cyr, P. / de Almeida Nagata, D. / Gascoigne, K.E. / Grogan, J.L. / Hatzivassiliou, G. / Huang, W. / Hunsaker, T.L. / Kaufman, S. / Koenig, S.G. / Li, R. / Li, Y. / Liang, X. / Liao, J. / Liu, W. / Ly, J. / Maher, J. / Masui, C. / Merchant, M. / Ran, Y. / Taylor, A.M. / Wai, J. / Wang, F. / Wei, X. / Yu, D. / Zhu, B.Y. / Zhu, X. / Magnuson, S.
History
DepositionMay 31, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 7, 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)36,2814
Polymers35,2602
Non-polymers1,0212
Water4,378243
1
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,1412
Polymers17,6301
Non-polymers5111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,1412
Polymers17,6301
Non-polymers5111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)49.648, 34.055, 80.887
Angle α, β, γ (deg.)90.000, 90.010, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein CREB-binding protein


Mass: 17629.973 Da / Num. of mol.: 2 / Fragment: Bromodomain, UNP residues 1082-1197
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-9UD / 1-{3-[7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl]-1-(oxan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl}ethan-1-one


Mass: 510.579 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H32F2N6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 243 / 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: 1.94 Å3/Da / Density % sol: 36.58 % / Mosaicity: 0.554 °
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 6.5
Details: 100 mM Bis-Tris pH 5.5, 200-300 mM KSCN, 21-25% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 27, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.5→28.083 Å / Num. obs: 39427 / % possible obs: 99.1 % / Redundancy: 3.5 % / Biso Wilson estimate: 16.41 Å2 / Rmerge(I) obs: 0.103 / Rpim(I) all: 0.066 / Rrim(I) all: 0.123 / Χ2: 1.021 / Net I/σ(I): 6.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.55-1.613.50.6030.8240.3790.7140.95199.8
1.61-1.673.50.4760.8830.2980.5631.02299.8
1.67-1.753.50.3870.9050.2420.4581.06299.9
1.75-1.843.50.2780.9490.1740.3291.05799.8
1.84-1.953.50.2230.9630.140.2641.05499.8
1.95-2.13.50.1630.9740.1030.1941.03599.5
2.1-2.323.50.1310.9790.0830.1561.07599.2
2.32-2.653.50.110.9850.070.131.00399.1
2.65-3.343.40.0860.9890.0570.1030.97897
3.34-303.30.0680.9920.0460.0830.96597.4

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Phasing

PhasingMethod: molecular replacement

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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: 1.549→28.083 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.93
RfactorNum. reflection% reflection
Rfree0.2294 2077 5.28 %
Rwork0.1925 --
obs0.1944 39371 98.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 65.23 Å2 / Biso mean: 23.0636 Å2 / Biso min: 11.12 Å2
Refinement stepCycle: final / Resolution: 1.549→28.083 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1908 0 74 243 2225
Biso mean--23.81 34.39 -
Num. residues----228
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082046
X-RAY DIFFRACTIONf_angle_d1.0192792
X-RAY DIFFRACTIONf_chiral_restr0.058284
X-RAY DIFFRACTIONf_plane_restr0.008406
X-RAY DIFFRACTIONf_dihedral_angle_d18.7651274
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5492-1.58530.31551470.25592410255798
1.5853-1.62490.24511770.236724732650100
1.6249-1.66880.23841410.21322432257399
1.6688-1.71790.25961030.215325492652100
1.7179-1.77340.27841300.202624752605100
1.7734-1.83670.23071120.18725212633100
1.8367-1.91030.27971580.199724822640100
1.9103-1.99720.17871280.184824872615100
1.9972-2.10240.21921440.180524972641100
2.1024-2.23410.19911010.17662501260299
2.2341-2.40650.2241490.1892505265499
2.4065-2.64850.22731610.1982487264899
2.6485-3.03140.26431350.20732451258698
3.0314-3.81770.20891730.18612455262897
3.8177-28.08790.22581180.1812569268797
Refinement TLS params.

S33: 0 Å ° / 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 °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.07550.111-0.11051.3287-0.73981.7811-0.0019-0.0268-0.02340.03490.04890.02920.0027-0.12920.1391-0.0091-0.00490.1118-0.00710.1255-9.3086-7.5788-33.82
20.791-0.09570.31761.2983-0.70771.9290.00370.01980.0058-0.05340.05950.06540.0223-0.12060.14770.0054-0.01060.1226-0.01070.1417-34.1473-18.0645-6.6165
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resseq 1084:1194)A1084 - 1194
2X-RAY DIFFRACTION2chain 'B' and (resseq 1084:1194)B1084 - 1194

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