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- PDB-8dd5: Crystal structure of KAT6A in complex with inhibitor CTx-648 (PF-9363) -

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Basic information

Entry
Database: PDB / ID: 8dd5
TitleCrystal structure of KAT6A in complex with inhibitor CTx-648 (PF-9363)
ComponentsHistone acetyltransferase KAT6A
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / histone lysine aceyltransferase / Inhibitor complex / Cancer / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


histone H4K12 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H4K16 acetyltransferase activity / histone H3 acetyltransferase activity / myeloid cell differentiation / regulation of developmental process / regulation of hemopoiesis / MOZ/MORF histone acetyltransferase complex ...histone H4K12 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H4K16 acetyltransferase activity / histone H3 acetyltransferase activity / myeloid cell differentiation / regulation of developmental process / regulation of hemopoiesis / MOZ/MORF histone acetyltransferase complex / protein acetylation / acetyltransferase activity / chromosome organization / histone acetyltransferase activity / histone acetyltransferase / Regulation of TP53 Activity through Acetylation / regulation of signal transduction by p53 class mediator / transcription coregulator activity / PML body / cellular senescence / nucleosome / nucleosome assembly / HATs acetylate histones / DNA-binding transcription factor binding / transcription coactivator activity / nuclear speck / negative regulation of DNA-templated transcription / chromatin binding / positive regulation of gene expression / regulation of DNA-templated transcription / nucleolus / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / positive regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
: / SAM domain-containing protein 1, WH domain / SAMD1-like winged helix (WH) domain profile. / MYST, zinc finger domain / MYST family zinc finger domain / Histone acetyltransferase domain, MYST-type / MOZ/SAS family / MYST-type histone acetyltransferase (HAT) domain profile. / Linker histone H1/H5, domain H15 / Linker histone H1/H5 globular (H15) domain profile. ...: / SAM domain-containing protein 1, WH domain / SAMD1-like winged helix (WH) domain profile. / MYST, zinc finger domain / MYST family zinc finger domain / Histone acetyltransferase domain, MYST-type / MOZ/SAS family / MYST-type histone acetyltransferase (HAT) domain profile. / Linker histone H1/H5, domain H15 / Linker histone H1/H5 globular (H15) domain profile. / Domain in histone families 1 and 5 / PHD-finger / Acyl-CoA N-acyltransferase / Zinc finger PHD-type signature. / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Zinc finger, RING/FYVE/PHD-type / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Chem-R7L / Histone acetyltransferase KAT6A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.58 Å
AuthorsGreasley, S.E. / Johnson, E. / Brodsky, O.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363
Authors: Sharma, S. / Chung, J. / Uryu, S. / Rickard, A. / Nady, N. / Cao, J. / Greasley, S.E. / Brodsky, O. / Khan, S. / Wang, H. / Wang, Z. / Zhang, Y. / Tsaparikos, K. / Chen, L. / Mazurek, A. / ...Authors: Sharma, S. / Chung, J. / Uryu, S. / Rickard, A. / Nady, N. / Cao, J. / Greasley, S.E. / Brodsky, O. / Khan, S. / Wang, H. / Wang, Z. / Zhang, Y. / Tsaparikos, K. / Chen, L. / Mazurek, A. / Lapek, J. / Kung, P.P. / Sutton, S. / Richardson, P.A. / Greenwald, E. / Yamazaki, S. / Jones, R. / Maegley, K. / Bingham, P. / Lam, H. / Stupple, A.E. / Kamal, A. / Chueh, A. / Cuzzupe, A. / Morrow, B. / Ren, B. / Carrasco-Pozo, C. / Tan, T.W. / Bhuva, D. / Allan, E. / Surgenor, E. / Vaillant, F. / Pehlivanoglu, H. / Falk, H. / Whittle, J. / Newman, J.M. / Cursons, J. / Doherty, J.P. / White, K.L. / MacPherson, L. / Devlin, M. / Dennis, M.L. / Hattarki, M.K. / De Silva, M. / Camerino, M.A. / Butler, M.S. / Dolezal, O. / Pilling, P. / Foitzik, R. / Stupple, P.A. / Lagiakos, R. / Walker, S. / Hediyeh-Zadeh, S. / Nuttall, S. / Spall, S. / Charman, S.A. / Connor, T. / Peat, T.S. / Avery, V.M. / Bozikis, Y.E. / Yang, Y. / Zhang, M. / Monahan, B.J. / Voss, A.K. / Thomas, T. / Street, I.P. / Dawson, S.J. / Dawson, M. / Lindeman, G.J. / Davis, M. / Visvader, J.E. / Paul, T.A.
History
DepositionJun 17, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 5, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Histone acetyltransferase KAT6A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2413
Polymers33,7311
Non-polymers5102
Water181
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.630, 59.630, 209.890
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Histone acetyltransferase KAT6A / MOZ / YBF2/SAS3 / SAS2 and TIP60 protein 3 / MYST-3 / Monocytic leukemia zinc finger protein / Runt- ...MOZ / YBF2/SAS3 / SAS2 and TIP60 protein 3 / MYST-3 / Monocytic leukemia zinc finger protein / Runt-related transcription factor-binding protein 2 / Zinc finger protein 220


Mass: 33731.180 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KAT6A, MOZ, MYST3, RUNXBP2, ZNF220 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92794, histone acetyltransferase
#2: Chemical ChemComp-R7L / 2,6-dimethoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide


Mass: 444.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20N4O6S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.77 Å3/Da / Density % sol: 55.53 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 100 mM sodium chloride 100 mM HEPES (pH 6.64) 1.8 M ammonium sulfate
PH range: 6.64

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.58→57.36 Å / Num. obs: 9547 / % possible obs: 92.6 % / Redundancy: 12.3 % / Biso Wilson estimate: 91.15 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.128 / Rpim(I) all: 0.038 / Net I/σ(I): 15
Reflection shellResolution: 2.58→2.82 Å / Redundancy: 10.9 % / Mean I/σ(I) obs: 1.4 / Num. unique obs: 477 / CC1/2: 0.661 / Rpim(I) all: 0.634 / % possible all: 16.6

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Processing

Software
NameVersionClassification
BUSTERrefinement
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
autoPROCdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.58→57.36 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.896 / SU R Cruickshank DPI: 1.734 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 4.534 / SU Rfree Blow DPI: 0.364 / SU Rfree Cruickshank DPI: 0.363
RfactorNum. reflection% reflectionSelection details
Rfree0.263 448 4.69 %RANDOM
Rwork0.232 ---
obs0.233 9546 75.4 %-
Displacement parametersBiso max: 156.15 Å2 / Biso mean: 79.44 Å2 / Biso min: 36.73 Å2
Baniso -1Baniso -2Baniso -3
1-0.9996 Å20 Å20 Å2
2--0.9996 Å20 Å2
3----1.9992 Å2
Refine analyzeLuzzati coordinate error obs: 0.43 Å
Refinement stepCycle: final / Resolution: 2.58→57.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2253 0 51 1 2305
Biso mean--42.18 64.52 -
Num. residues----272
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d822SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes396HARMONIC5
X-RAY DIFFRACTIONt_it2367HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion287SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2670SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2367HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3216HARMONIC21.25
X-RAY DIFFRACTIONt_omega_torsion3.21
X-RAY DIFFRACTIONt_other_torsion21.04
LS refinement shellResolution: 2.58→2.81 Å / Rfactor Rfree error: 0 / Total num. of bins used: 22
RfactorNum. reflection% reflection
Rfree0.3893 16 3.69 %
Rwork0.2599 418 -
all0.2641 434 -
obs--16.16 %

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