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- PDB-9mza: Chemically Hijacked BCL6-TCIP3-p300 Complex -

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Basic information

Entry
Database: PDB / ID: 9mza
TitleChemically Hijacked BCL6-TCIP3-p300 Complex
Components
  • B-cell lymphoma 6 protein
  • Histone acetyltransferase p300
KeywordsTRANSCRIPTION / BCL6 / transcription factor / TCIP / small molecule / p300 / acetyltransferase / bromodomain / BTB domain / therapeutics
Function / homology
Function and homology information


behavioral defense response / negative regulation of protein oligomerization / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / swimming / peptide butyryltransferase activity / regulation of tubulin deacetylation ...behavioral defense response / negative regulation of protein oligomerization / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / swimming / peptide butyryltransferase activity / regulation of tubulin deacetylation / histone H2B acetyltransferase activity / internal protein amino acid acetylation / peptide 2-hydroxyisobutyryltransferase activity / histone crotonyltransferase activity / thigmotaxis / protein propionyltransferase activity / NOTCH2 intracellular domain regulates transcription / L-lysine N-acetyltransferase activity, acting on acetyl phosphate as donor / positive regulation of TORC2 signaling / internal peptidyl-lysine acetylation / histone H4 acetyltransferase activity / cellular response to L-leucine / histone H3 acetyltransferase activity / NFE2L2 regulating ER-stress associated genes / protein N-acetyltransferase activity / acetylation-dependent protein binding / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / NGF-stimulated transcription / regulation of memory T cell differentiation / negative regulation of mitotic cell cycle DNA replication / intronic transcription regulatory region sequence-specific DNA binding / negative regulation of isotype switching to IgE isotypes / negative regulation of plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / isotype switching to IgE isotypes / N-terminal peptidyl-lysine acetylation / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / negative regulation of mast cell cytokine production / STAT3 nuclear events downstream of ALK signaling / regulation of germinal center formation / negative regulation of mononuclear cell proliferation / Polo-like kinase mediated events / plasma cell differentiation / NFE2L2 regulating MDR associated enzymes / TGFBR3 expression / positive regulation by host of viral transcription / regulation of androgen receptor signaling pathway / regulation of mitochondrion organization / paraspeckles / germinal center formation / regulation of immune system process / 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 / pyramidal neuron differentiation / NOTCH4 Intracellular Domain Regulates Transcription / face morphogenesis / Regulation of NFE2L2 gene expression / type 2 immune response / Regulation of gene expression by Hypoxia-inducible Factor / T-helper 2 cell differentiation / platelet formation / positive regulation of regulatory T cell differentiation / NOTCH3 Intracellular Domain Regulates Transcription / regulation of glycolytic process / TRAF6 mediated IRF7 activation / NFE2L2 regulating tumorigenic genes / NFE2L2 regulating anti-oxidant/detoxification enzymes / negative regulation of B cell apoptotic process / megakaryocyte development / protein-lysine-acetyltransferase activity / STAT family protein binding / positive regulation of cell motility / nuclear androgen receptor binding / acyltransferase activity / protein acetylation / negative regulation of Rho protein signal transduction / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / histone acetyltransferase activity / acetyltransferase activity / PI5P Regulates TP53 Acetylation / FOXO-mediated transcription of cell death genes / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / fat cell differentiation / stimulatory C-type lectin receptor signaling pathway / Zygotic genome activation (ZGA) / regulation of cell differentiation / regulation of T cell proliferation / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / B cell proliferation / RUNX3 regulates p14-ARF / negative regulation of cellular senescence / histone acetyltransferase complex / negative regulation of cell-matrix adhesion / negative regulation of Notch signaling pathway / canonical NF-kappaB signal transduction
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. / BTB/POZ domain / BTB domain profile. / Zinc finger, C2H2 type / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / Nuclear receptor coactivator, interlocking / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / SKP1/BTB/POZ domain superfamily / Zinc finger C2H2-type / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
: / B-cell lymphoma 6 protein / Histone acetyltransferase p300
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsHinshaw, S.M. / Gray, N.S. / Nix, M.N. / Gourisankar, S. / Martinez, M. / Crabtree, G.R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA276167-02 United States
CitationJournal: Biorxiv / Year: 2025
Title: A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-induced Cell Death.
Authors: Nix, M.N. / Gourisankar, S. / Sarott, R.C. / Dwyer, B.G. / Nettles, S.A. / Martinez, M.M. / Abuzaid, H. / Yang, H. / Wang, Y. / Simanauskaite, J.M. / Romero, B.A. / Jones, H.M. / Krokhotin, ...Authors: Nix, M.N. / Gourisankar, S. / Sarott, R.C. / Dwyer, B.G. / Nettles, S.A. / Martinez, M.M. / Abuzaid, H. / Yang, H. / Wang, Y. / Simanauskaite, J.M. / Romero, B.A. / Jones, H.M. / Krokhotin, A. / Lowensohn, T.N. / Chen, L. / Low, C. / Davis, M.M. / Fernandez, D. / Zhang, T. / Green, M.R. / Hinshaw, S.M. / Gray, N.S. / Crabtree, G.R.
History
DepositionJan 22, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 16, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: B-cell lymphoma 6 protein
B: Histone acetyltransferase p300
C: B-cell lymphoma 6 protein
D: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,7806
Polymers63,5074
Non-polymers2,2732
Water7,710428
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: fluorescence resonance energy transfer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.388, 94.790, 97.616
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
32B
42D

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111SERSERALAALAAA7 - 1276 - 126
211SERSERALAALACC7 - 1276 - 126
322ILEILEGLNGLNBB1048 - 115832 - 142
422ILEILEGLNGLNDD1048 - 115832 - 142

NCS ensembles :
IDDetails
1Local NCS retraints between domains: 1 2
2Local NCS retraints between domains: 3 4

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Components

#1: Protein B-cell lymphoma 6 protein / BCL-6 / B-cell lymphoma 5 protein / BCL-5 / Protein LAZ-3 / Zinc finger and BTB domain-containing ...BCL-6 / B-cell lymphoma 5 protein / BCL-5 / Protein LAZ-3 / Zinc finger and BTB domain-containing protein 27 / Zinc finger protein 51


Mass: 14626.913 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL6, BCL5, LAZ3, ZBTB27, ZNF51 / Production host: Escherichia coli (E. coli) / References: UniProt: P41182
#2: Protein Histone acetyltransferase p300 / p300 HAT / E1A-associated protein p300 / Histone butyryltransferase p300 / Histone ...p300 HAT / E1A-associated protein p300 / Histone butyryltransferase p300 / Histone crotonyltransferase p300 / Protein 2-hydroxyisobutyryltransferase p300 / Protein lactyltransferas p300 / Protein propionyltransferase p300


Mass: 17126.461 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EP300, P300 / Production host: Escherichia coli (E. coli)
References: UniProt: Q09472, histone acetyltransferase, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#3: Chemical ChemComp-A1BUC / 1-{1-[5-({1-[5-chloro-4-({8-methoxy-1-methyl-3-[2-(methylamino)-2-oxoethoxy]-2-oxo-1,2-dihydroquinolin-6-yl}amino)pyrimidin-2-yl]piperidine-4-carbonyl}amino)pentanoyl]piperidin-4-yl}-3-[(6M)-7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl]-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide


Mass: 1136.685 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C56H68ClF2N15O7 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 428 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.78 Å3/Da / Density % sol: 55.79 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / Details: 0.15 M DL-Malic acid pH 7.0, PEG 3,350 20%

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 15, 2023
Details: Rh coated flat bent M0, toroidal focusing post-monochromator M1
RadiationMonochromator: Si(111) and Si(220) double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.01→60.16 Å / Num. obs: 47662 / % possible obs: 99.2 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.122 / Net I/σ(I): 6.7
Reflection shellResolution: 2.01→2.06 Å / Rmerge(I) obs: 1.764 / Num. unique obs: 3471 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0430refinement
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→60 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.935 / SU B: 10.971 / SU ML: 0.239 / Cross valid method: FREE R-VALUE / ESU R: 0.212 / ESU R Free: 0.2
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2765 2021 4.854 %
Rwork0.2175 39619 -
all0.22 --
obs-41640 98.933 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 47.937 Å2
Baniso -1Baniso -2Baniso -3
1-6.775 Å20 Å20 Å2
2---4.123 Å20 Å2
3----2.652 Å2
Refinement stepCycle: LAST / Resolution: 2.1→60 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3884 0 162 428 4474
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0124172
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163964
X-RAY DIFFRACTIONr_angle_refined_deg1.7091.8315669
X-RAY DIFFRACTIONr_angle_other_deg0.571.7619118
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3895472
X-RAY DIFFRACTIONr_dihedral_angle_2_deg18.8337.24158
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.13110732
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.33910199
X-RAY DIFFRACTIONr_chiral_restr0.0790.2607
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024869
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02979
X-RAY DIFFRACTIONr_nbd_refined0.2370.21078
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1990.24062
X-RAY DIFFRACTIONr_nbtor_refined0.1930.22105
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.080.22288
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.230.2330
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1240.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.0850.222
X-RAY DIFFRACTIONr_nbd_other0.1780.252
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1190.219
X-RAY DIFFRACTIONr_mcbond_it4.6674.9641888
X-RAY DIFFRACTIONr_mcbond_other4.6674.9651888
X-RAY DIFFRACTIONr_mcangle_it6.6988.8922357
X-RAY DIFFRACTIONr_mcangle_other6.6988.8942358
X-RAY DIFFRACTIONr_scbond_it5.5775.462284
X-RAY DIFFRACTIONr_scbond_other5.5775.462284
X-RAY DIFFRACTIONr_scangle_it8.5569.8033311
X-RAY DIFFRACTIONr_scangle_other8.5559.8023312
X-RAY DIFFRACTIONr_lrange_it11.366217898
X-RAY DIFFRACTIONr_lrange_other11.34761.91917496
X-RAY DIFFRACTIONr_ncsr_local_group_10.0810.053987
X-RAY DIFFRACTIONr_ncsr_local_group_20.10.053956
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.081430.05009
12CX-RAY DIFFRACTIONLocal ncs0.081430.05009
23BX-RAY DIFFRACTIONLocal ncs0.100280.0501
24DX-RAY DIFFRACTIONLocal ncs0.100280.0501
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.1540.4131500.4582869X-RAY DIFFRACTION98.0513
2.154-2.2130.4081490.4252782X-RAY DIFFRACTION98.191
2.213-2.2780.4081480.3842727X-RAY DIFFRACTION99.3092
2.278-2.3480.3321480.3532654X-RAY DIFFRACTION99.3617
2.348-2.4240.371310.3332595X-RAY DIFFRACTION99.2717
2.424-2.5090.3371220.3012506X-RAY DIFFRACTION99.4701
2.509-2.6040.2651250.272442X-RAY DIFFRACTION99.612
2.604-2.710.3461120.2442348X-RAY DIFFRACTION99.1136
2.71-2.830.3291050.2482195X-RAY DIFFRACTION96.5575
2.83-2.9680.3071290.2062143X-RAY DIFFRACTION99.7804
2.968-3.1280.2571050.1982043X-RAY DIFFRACTION99.7215
3.128-3.3170.2511210.1991935X-RAY DIFFRACTION99.7574
3.317-3.5460.271690.1941881X-RAY DIFFRACTION99.8975
3.546-3.8290.23910.1681706X-RAY DIFFRACTION99.4466
3.829-4.1920.238660.1371540X-RAY DIFFRACTION95.8234
4.192-4.6840.194730.1271448X-RAY DIFFRACTION99.6723
4.684-5.4040.187730.1311282X-RAY DIFFRACTION99.486
5.404-6.6050.278480.1671101X-RAY DIFFRACTION99.1372
6.605-9.2850.308240.134878X-RAY DIFFRACTION97.4082
9.285-600.2310.164532X-RAY DIFFRACTION99.2945

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