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- PDB-5ktu: Crystal structure of the bromodomain of human CREBBP bound to pyr... -

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Basic information

Entry
Database: PDB / ID: 5ktu
TitleCrystal structure of the bromodomain of human CREBBP bound to pyrazolopiperidine scaffold
ComponentsCREB-binding protein
KeywordsTRANSFERASE / bromodomain / inhibitor / epigenetics
Function / homology
Function and homology information


peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / histone H3K18 acetyltransferase activity / 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 / regulation of smoothened signaling pathway ...peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / histone H3K18 acetyltransferase activity / 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 / regulation of smoothened signaling pathway / 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 / Regulation of FOXO transcriptional activity by acetylation / RUNX3 regulates NOTCH signaling / NOTCH4 Intracellular Domain Regulates Transcription / Nuclear events mediated by NFE2L2 / 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 / embryonic digit morphogenesis / protein-lysine-acetyltransferase activity / protein acetylation / homeostatic process / Notch-HLH transcription pathway / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / 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 / Attenuation phase / histone acetyltransferase activity / cellular response to nutrient levels / histone acetyltransferase / positive regulation of double-strand break repair via homologous recombination / regulation of cellular response to heat / : / NPAS4 regulates expression of target genes / Regulation of lipid metabolism by PPARalpha / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / Transcriptional and post-translational regulation of MITF-M expression and activity / CD209 (DC-SIGN) signaling / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / Heme signaling / Transcriptional activation of mitochondrial biogenesis / Formation of the beta-catenin:TCF transactivating complex / PPARA activates gene expression / Cytoprotection by HMOX1 / protein destabilization / chromatin DNA binding / Evasion by RSV of host interferon responses / NOTCH1 Intracellular Domain Regulates Transcription / Transcriptional regulation of white adipocyte differentiation / positive regulation of protein localization to nucleus / Pre-NOTCH Transcription and Translation / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / transcription coactivator binding / tau protein binding / Activation of anterior HOX genes in hindbrain development during early embryogenesis / p53 binding / cellular response to UV / : / transcription corepressor activity / rhythmic process / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / TRAF3-dependent IRF activation pathway / protein-containing complex assembly / transcription regulator complex / DNA-binding transcription factor binding / Estrogen-dependent gene expression / damaged DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / transcription coactivator activity / response to hypoxia / nuclear body / chromatin binding / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / SARS-CoV-2 activates/modulates innate and adaptive immune responses / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / 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 / : / Histone acetyltransferase p300-like, PHD 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 / : / Histone acetyltransferase p300-like, PHD domain / 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 / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-6XB / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.38 Å
AuthorsJayaram, H. / Poy, F. / Setser, J.W. / Bellon, S.F.
CitationJournal: J. Med. Chem. / Year: 2016
Title: Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.
Authors: Crawford, T.D. / Romero, F.A. / Lai, K.W. / Tsui, V. / Taylor, A.M. / de Leon Boenig, G. / Noland, C.L. / Murray, J. / Ly, J. / Choo, E.F. / Hunsaker, T.L. / Chan, E.W. / Merchant, M. / ...Authors: Crawford, T.D. / Romero, F.A. / Lai, K.W. / Tsui, V. / Taylor, A.M. / de Leon Boenig, G. / Noland, C.L. / Murray, J. / Ly, J. / Choo, E.F. / Hunsaker, T.L. / Chan, E.W. / Merchant, M. / Kharbanda, S. / Gascoigne, K.E. / Kaufman, S. / Beresini, M.H. / Liao, J. / Liu, W. / Chen, K.X. / Chen, Z. / Conery, A.R. / Cote, A. / Jayaram, H. / Jiang, Y. / Kiefer, J.R. / Kleinheinz, T. / Li, Y. / Maher, J. / Pardo, E. / Poy, F. / Spillane, K.L. / Wang, F. / Wang, J. / Wei, X. / Xu, Z. / Xu, Z. / Yen, I. / Zawadzke, L. / Zhu, X. / Bellon, S. / Cummings, R. / Cochran, A.G. / Albrecht, B.K. / Magnuson, S.
History
DepositionJul 12, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2016Group: Database references
Revision 1.2Oct 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_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)28,3184
Polymers27,9842
Non-polymers3342
Water3,873215
1
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,2482
Polymers13,9921
Non-polymers2561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0702
Polymers13,9921
Non-polymers781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)125.220, 125.220, 39.789
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: MET / Beg label comp-ID: MET / End auth comp-ID: ASP / End label comp-ID: ASP / Refine code: 4 / Auth seq-ID: 1095 - 1190 / Label seq-ID: 16 - 111

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.142701, -0.561357, -0.815177), (-0.709119, -0.632564, 0.311469), (-0.690497, 0.533611, -0.488337)117.394341, 244.67215, -38.849548

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Components

#1: Protein CREB-binding protein


Mass: 13992.011 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-6XB / 1-(3-phenylazanyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone


Mass: 256.303 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H16N4O
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 215 / 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: 2.22 Å3/Da / Density % sol: 44.55 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.2 M magnesium chloride, 0.1 M Bis-Tris pH 6.5, and 25% polyethylene glycol (PEG) 3350
Temp details: cold room

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9786 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Dec 1, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.38→62.61 Å / Num. obs: 47773 / % possible obs: 99.7 % / Redundancy: 4.6 % / Rsym value: 0.061 / Net I/σ(I): 22.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0069refinement
PDB_EXTRACT3.2data extraction
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3DWY

3dwy


Resolution: 1.38→62.61 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.959 / SU B: 2.283 / SU ML: 0.047 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.064 / ESU R Free: 0.064
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2122 2422 5.1 %RANDOM
Rwork0.1915 ---
obs0.1926 45351 99.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 97.35 Å2 / Biso mean: 26.338 Å2 / Biso min: 11.71 Å2
Baniso -1Baniso -2Baniso -3
1--0.35 Å2-0.17 Å20 Å2
2---0.35 Å20 Å2
3---1.13 Å2
Refinement stepCycle: final / Resolution: 1.38→62.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1854 0 23 215 2092
Biso mean--23.08 31.88 -
Num. residues----220
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.021956
X-RAY DIFFRACTIONr_bond_other_d00.021841
X-RAY DIFFRACTIONr_angle_refined_deg1.4211.9872662
X-RAY DIFFRACTIONr_angle_other_deg0.7373.0034252
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2735224
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.06724.7100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.44915342
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1181512
X-RAY DIFFRACTIONr_chiral_restr0.0890.2277
X-RAY DIFFRACTIONr_gen_planes_refined0.020.0212192
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02451
X-RAY DIFFRACTIONr_mcbond_it2.1551.616893
X-RAY DIFFRACTIONr_mcbond_other2.0881.613892
X-RAY DIFFRACTIONr_mcangle_it2.7442.4121118
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Number: 1556 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
MEDIUM POSITIONAL0.570.5
MEDIUM THERMAL3.992
LS refinement shellResolution: 1.379→1.415 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.261 190 -
Rwork0.287 3301 -
all-3491 -
obs--98.62 %
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)
11.1908-0.31070.36843.21981.33041.7202-0.02650.1174-0.0209-0.34590.1269-0.081-0.1210.1508-0.10040.1111-0.0295-0.00590.0233-0.0060.019747.7018115.5587-4.7012
21.3289-0.77450.3371.001-0.6020.81720.03380.02470.0914-0.0259-0.04-0.11940.01320.04980.00610.01430.00450.00130.0256-0.01890.047159.2527138.74310.154
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1089 - 1195
2X-RAY DIFFRACTION2B1084 - 1196

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