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- PDB-6lqx: Crystal structure of the CBP bromodomain in complex with small mo... -

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Basic information

Entry
Database: PDB / ID: 6lqx
TitleCrystal structure of the CBP bromodomain in complex with small molecule LC-CPin7
ComponentsCREB-binding protein
KeywordsTRANSFERASE / inhibitor / CBP / p300 / Bromodomain / LC-CPin7
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 / NFE2L2 regulating MDR associated enzymes / MRF binding / 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 / histone acetyltransferase / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / 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 / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / transcription coregulator activity / 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, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-EOO / histone acetyltransferase / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.46 Å
AuthorsChen, Y. / Zhang, F. / Sun, Z. / Bi, X. / Luo, C.
CitationJournal: To Be Published
Title: Design, synthesis and biological evaluation of novel small molecule inhibitor of the CBP bromodomain with possible anti-leukemia effects
Authors: Chen, Y. / Bi, X. / Zhang, F. / Sun, Z. / Luo, C.
History
DepositionJan 14, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 29, 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

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Assembly

Deposited unit
B: CREB-binding protein
A: CREB-binding protein
D: CREB-binding protein
C: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,66011
Polymers55,1634
Non-polymers4967
Water3,315184
1
B: CREB-binding protein
hetero molecules

C: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0327
Polymers27,5822
Non-polymers4505
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_455x-1,y,z1
Buried area2600 Å2
ΔGint-59 kcal/mol
Surface area11890 Å2
MethodPISA
2
A: CREB-binding protein
D: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,6284
Polymers27,5822
Non-polymers462
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2430 Å2
ΔGint-38 kcal/mol
Surface area12190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.890, 68.789, 76.669
Angle α, β, γ (deg.)90.000, 91.748, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein
CREB-binding protein /


Mass: 13790.830 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP / Production host: Escherichia coli (E. coli) / References: UniProt: I3L466, UniProt: Q92793*PLUS
#2: Chemical ChemComp-EOO / (1~{S},6~{R})-6-[(1-methoxycarbonyl-3,4-dihydro-2~{H}-quinolin-6-yl)carbamoyl]cyclohex-3-ene-1-carboxylic acid


Mass: 358.388 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22N2O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 184 / 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: 2.14 Å3/Da / Density % sol: 42.65 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 4.7
Details: 0.2 M Sodium phosphate monobasic monohydrate;20% w/v Polyethylene glycol 3,350;Ph 4.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97852 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 16, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 2.46→38.22 Å / Num. obs: 16809 / % possible obs: 98.36 % / Redundancy: 6.5 % / Biso Wilson estimate: 26.3 Å2 / Rmerge(I) obs: 0.177 / Net I/σ(I): 9.5
Reflection shellResolution: 2.46→2.548 Å / Num. unique obs: 1643 / CC1/2: 0.885

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4UOF

4uof


Resolution: 2.46→38.22 Å / SU ML: 0.3388 / Cross valid method: FREE R-VALUE / σ(F): 1.4 / Phase error: 26.0448 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.2602 784 4.66 %
Rwork0.1706 16024 -
obs0.1747 16808 98.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.76 Å2
Refinement stepCycle: LAST / Resolution: 2.46→38.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3838 0 32 184 4054
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00813973
X-RAY DIFFRACTIONf_angle_d0.91895395
X-RAY DIFFRACTIONf_chiral_restr0.0477564
X-RAY DIFFRACTIONf_plane_restr0.0069698
X-RAY DIFFRACTIONf_dihedral_angle_d19.11692434
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.46-2.610.3758860.22062658X-RAY DIFFRACTION97.79
2.61-2.820.30881530.20622680X-RAY DIFFRACTION99.06
2.82-3.10.26491580.18192627X-RAY DIFFRACTION99.29
3.1-3.550.27161180.16792629X-RAY DIFFRACTION96.52
3.55-4.470.20641120.14062745X-RAY DIFFRACTION99.76
4.47-38.220.24491570.16462685X-RAY DIFFRACTION97.93

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