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- PDB-9fkr: KAT6A IN COMPLEX WITH SMALL MOLECULE INHIBITOR BAY-184 -

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Basic information

Entry
Database: PDB / ID: 9fkr
TitleKAT6A IN COMPLEX WITH SMALL MOLECULE INHIBITOR BAY-184
ComponentsHistone acetyltransferase KAT6A
KeywordsTRANSFERASE / HISTONE ACETYLTRANSFERASE / SMALL MOLECULE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX / TRANSCRIPTION
Function / homology
Function and homology information


histone H3 acetyltransferase activity / myeloid cell differentiation / MOZ/MORF histone acetyltransferase complex / regulation of developmental process / regulation of hemopoiesis / protein acetylation / histone acetyltransferase activity / acetyltransferase activity / chromosome organization / histone H4K16 acetyltransferase activity ...histone H3 acetyltransferase activity / myeloid cell differentiation / MOZ/MORF histone acetyltransferase complex / regulation of developmental process / regulation of hemopoiesis / protein acetylation / histone acetyltransferase activity / acetyltransferase activity / chromosome organization / 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 / 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 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 / regulation of transcription by RNA polymerase II / chromatin / positive regulation of DNA-templated transcription / nucleolus / 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 ...: / 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
: / Histone acetyltransferase KAT6A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.69 Å
AuthorsHillig, R.C. / Puetter, V.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo -Active KAT6AB Inhibitor.
Authors: Ter Laak, A. / Hillig, R.C. / Ferrara, S.J. / Korr, D. / Barak, N. / Lienau, P. / Herbert, S. / Fernandez-Montalvan, A.E. / Neuhaus, R. / Gorjanacz, M. / Puetter, V. / Badock, V. / Bone, W. ...Authors: Ter Laak, A. / Hillig, R.C. / Ferrara, S.J. / Korr, D. / Barak, N. / Lienau, P. / Herbert, S. / Fernandez-Montalvan, A.E. / Neuhaus, R. / Gorjanacz, M. / Puetter, V. / Badock, V. / Bone, W. / Strathdee, C. / Siegel, F. / Schatz, C. / Nowak-Reppel, K. / Doehr, O. / Gradl, S. / Hartung, I.V. / Meyerson, M. / Bouche, L.
History
DepositionJun 4, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone acetyltransferase KAT6A
B: Histone acetyltransferase KAT6A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,7958
Polymers64,3462
Non-polymers1,4486
Water75742
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, monomer in gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3390 Å2
ΔGint7 kcal/mol
Surface area26900 Å2
Unit cell
Length a, b, c (Å)37.805, 59.921, 65.850
Angle α, β, γ (deg.)92.22, 90.82, 103.20
Int Tables number1
Space group name H-MP1

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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: 32173.229 Da / Num. of mol.: 2 / Mutation: R507G, C508S, C638S, C646S, C723S, C773S
Source method: isolated from a genetically manipulated source
Details: R507G, C508S are cloning artifacts, from TEV cleavage site. C638S, C646S, C723S, C773S are engineered.
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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: Zn
#3: Chemical ChemComp-A1IDR / 6-(dimethylamino)-~{N}-(2-phenylphenyl)sulfonyl-1-benzofuran-2-carboxamide


Mass: 420.481 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H20N2O4S
#4: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 42 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.25 Å3/Da / Density % sol: 45.45 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: RESERVOIR 100 MILLIMOLAR HEPES PH 7.1-7.5, 17-21% PEG 3350 (W/V). PROTEIN CONCENTRATION 7.1 MG/ML, PROTEIN PREINCUBATED WITH 4 MILLIMOLAR ACETYL-COA. DROPS MADE FROM 0.8 MICROLITER PROTEIN ...Details: RESERVOIR 100 MILLIMOLAR HEPES PH 7.1-7.5, 17-21% PEG 3350 (W/V). PROTEIN CONCENTRATION 7.1 MG/ML, PROTEIN PREINCUBATED WITH 4 MILLIMOLAR ACETYL-COA. DROPS MADE FROM 0.8 MICROLITER PROTEIN AND 0.8 MICROLITER RESERVOIR SOLUTION. CRYSTAL WASHED IN RESERVOIR SOLUTION, THEN COMPOUND BACKSOAKED FOR 10 DAYS AT 10 MILLIMOLAR.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 25, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.69→65.79 Å / Num. obs: 15260 / % possible obs: 97.4 % / Redundancy: 3.5 % / Biso Wilson estimate: 68.2 Å2 / CC1/2: 0.997 / Rrim(I) all: 0.101 / Rsym value: 0.086 / Net I/σ(I): 11.5
Reflection shellResolution: 2.69→2.85 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 1.09 / Num. unique obs: 2317 / CC1/2: 0.606 / Rrim(I) all: 1.307 / Rsym value: 1.188 / % possible all: 91.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
pointless1.10.18data scaling
XDSVERSION Nov 11, 2017data reduction
PHASER2.7.17phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.69→44.63 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.938 / SU B: 33.966 / SU ML: 0.322 / Cross valid method: THROUGHOUT / ESU R Free: 0.365 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23766 763 5 %RANDOM
Rwork0.19703 ---
obs0.199 14496 97.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 73.1 Å2
Baniso -1Baniso -2Baniso -3
1-0.49 Å2-0.4 Å2-0.22 Å2
2---0.02 Å20.09 Å2
3----0.28 Å2
Refinement stepCycle: 1 / Resolution: 2.69→44.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4343 0 76 42 4461
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0134579
X-RAY DIFFRACTIONr_bond_other_d0.0010.0154287
X-RAY DIFFRACTIONr_angle_refined_deg1.2681.6716200
X-RAY DIFFRACTIONr_angle_other_deg1.0321.5839855
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4585524
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.59421.845233
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.84215803
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4611524
X-RAY DIFFRACTIONr_chiral_restr0.0480.2557
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025031
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021061
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9134.1252096
X-RAY DIFFRACTIONr_mcbond_other2.9134.1252095
X-RAY DIFFRACTIONr_mcangle_it4.8339.2672614
X-RAY DIFFRACTIONr_mcangle_other4.8339.2672615
X-RAY DIFFRACTIONr_scbond_it3.3334.4122483
X-RAY DIFFRACTIONr_scbond_other3.3244.4042481
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.4169.7733585
X-RAY DIFFRACTIONr_long_range_B_refined7.75347.894788
X-RAY DIFFRACTIONr_long_range_B_other7.75847.9164789
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 8122 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.09 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.69→2.756 Å
RfactorNum. reflection% reflection
Rfree0.494 48 -
Rwork0.419 920 -
obs--83.74 %
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)
12.2720.02390.79063.2885-0.37663.82950.1375-0.0830.1373-0.1389-0.06990.08940.46570.0475-0.06760.0693-0.01330.05950.0456-0.1490.5073-10.67529.269-15.965
22.49160.721.10912.17171.63438.44510.12940.5162-0.0786-0.4249-0.1210.12690.86320.4348-0.00840.44340.12330.13250.1701-0.07440.2356-8.88927.44-43.227
32.4921.1721-0.03893.48520.74693.16760.0948-0.18090.03770.00050.0275-0.0428-0.26960.2783-0.12240.0313-0.04410.06390.0798-0.16770.5697-5.42857.613-7.109
41.58320.10380.09531.15450.92736.72150.2595-0.4193-0.25960.6102-0.2344-0.2159-0.37350.3406-0.02510.6461-0.2225-0.04220.509-0.04850.5695-3.93157.87719.239
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A507 - 679
2X-RAY DIFFRACTION2A680 - 778
3X-RAY DIFFRACTION3B507 - 679
4X-RAY DIFFRACTION4B680 - 778

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