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- PDB-9cr7: Structure of human SETD8 in complex with covalent inhibitor AM2928 -

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Basic information

Entry
Database: PDB / ID: 9cr7
TitleStructure of human SETD8 in complex with covalent inhibitor AM2928
ComponentsN-lysine methyltransferase KMT5A
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / SETD8 / Lysine methyltransferase / KMT / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


lysine N-methyltransferase activity / histone H4K20 monomethyltransferase activity / [histone H4]-lysine20 N-methyltransferase / histone H4K20 methyltransferase activity / histone H4 methyltransferase activity / peptidyl-lysine monomethylation / polytene chromosome / mitotic chromosome condensation / protein-lysine N-methyltransferase activity / regulation of DNA damage response, signal transduction by p53 class mediator ...lysine N-methyltransferase activity / histone H4K20 monomethyltransferase activity / [histone H4]-lysine20 N-methyltransferase / histone H4K20 methyltransferase activity / histone H4 methyltransferase activity / peptidyl-lysine monomethylation / polytene chromosome / mitotic chromosome condensation / protein-lysine N-methyltransferase activity / regulation of DNA damage response, signal transduction by p53 class mediator / histone methyltransferase activity / negative regulation of double-strand break repair via homologous recombination / Transferases; Transferring one-carbon groups; Methyltransferases / regulation of signal transduction by p53 class mediator / Condensation of Prophase Chromosomes / Regulation of TP53 Activity through Methylation / PKMTs methylate histone lysines / transcription corepressor activity / cell division / negative regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / chromatin / negative regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / cytosol
Similarity search - Function
Class V SAM-dependent methyltransferases / Histone-lysine N-methyltransferase (EC 2.1.1.43) family profile. / : / : / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain profile. / SET domain superfamily / SET domain
Similarity search - Domain/homology
Chem-E1J / : / N-lysine methyltransferase KMT5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MIR / Resolution: 2.05 Å
AuthorsBabault, N. / Park, K.S. / Jin, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01GM122749 United States
CitationJournal: To be published
Title: Structure-Activity relationship studies of SETD8 covalent inhibitors
Authors: Ma, A. / Babault, N. / Hong, W. / Dong, A. / Hong, Z. / Xin, C. / Park, K.S. / Brown, P.J. / Liu, J. / Vedadi, M. / Jin, J.
History
DepositionJul 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 30, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: N-lysine methyltransferase KMT5A
B: N-lysine methyltransferase KMT5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,3444
Polymers40,5172
Non-polymers8272
Water1,76598
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)35.715, 102.457, 110.713
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein N-lysine methyltransferase KMT5A / H4-K20-HMTase KMT5A / Histone-lysine N-methyltransferase KMT5A / Lysine N-methyltransferase 5A / ...H4-K20-HMTase KMT5A / Histone-lysine N-methyltransferase KMT5A / Lysine N-methyltransferase 5A / Lysine-specific methylase 5A / PR/SET domain-containing protein 07 / PR-Set7 / PR/SET07 / SET domain-containing protein 8


Mass: 20258.654 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KMT5A, PRSET7, SET07, SET8, SETD8 / Plasmid: pHIS2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): codon plus RIL
References: UniProt: Q9NQR1, Transferases; Transferring one-carbon groups; Methyltransferases, [histone H4]-lysine20 N-methyltransferase
#2: Chemical ChemComp-E1J / N-(3-{[7-(2-aminoethoxy)-6-methoxy-2-(pyrrolidin-1-yl)quinazolin-4-yl]amino}propyl)prop-2-enamide


Mass: 414.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N6O3
#3: Chemical ChemComp-H81 / N-(3-{[7-(2-aminoethoxy)-6-methoxy-2-(pyrrolidin-1-yl)quinazolin-4-yl]amino}propyl)prop-2-ynamide


Mass: 412.485 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 2.68 Å3/Da / Density % sol: 54.11 %
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 7.5 / Details: 20% PEG 3350 and 0.2 M Lithium Nitrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 19, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.05→110.71 Å / Num. obs: 26231 / % possible obs: 99.4 % / Redundancy: 12.7 % / CC1/2: 1 / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.015 / Rrim(I) all: 0.053 / Net I/σ(I): 22.1 / Num. measured all: 333480
Reflection shellResolution: 2.05→2.16 Å / % possible obs: 97 % / Redundancy: 12.7 % / Rmerge(I) obs: 0.781 / Num. measured all: 46155 / Num. unique obs: 3645 / CC1/2: 0.933 / Rpim(I) all: 0.226 / Rrim(I) all: 0.814 / Net I/σ(I) obs: 3.1

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Processing

Software
NameVersionClassification
PHENIX(1.21_5207: ???)refinement
SCALA3.3.22data scaling
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MIR / Resolution: 2.05→55.36 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.21 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2326 1341 5.13 %
Rwork0.2128 --
obs0.2139 26147 99.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.05→55.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2241 0 60 98 2399
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042351
X-RAY DIFFRACTIONf_angle_d0.6093156
X-RAY DIFFRACTIONf_dihedral_angle_d20.073912
X-RAY DIFFRACTIONf_chiral_restr0.043332
X-RAY DIFFRACTIONf_plane_restr0.004405
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.120.29121250.28422358X-RAY DIFFRACTION95
2.12-2.210.28091260.27522419X-RAY DIFFRACTION100
2.21-2.310.30351200.27522452X-RAY DIFFRACTION99
2.31-2.430.34941280.2872442X-RAY DIFFRACTION99
2.43-2.580.35871410.30752463X-RAY DIFFRACTION100
2.58-2.780.291260.27442484X-RAY DIFFRACTION100
2.78-3.060.26821350.26192476X-RAY DIFFRACTION100
3.06-3.50.25561470.23052503X-RAY DIFFRACTION100
3.51-4.420.19421280.18372557X-RAY DIFFRACTION100
4.42-55.360.19751650.1722652X-RAY DIFFRACTION100
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)
10.3985-0.12060.03360.2858-0.37420.2623-0.0305-0.88390.3297-0.14640.4112-0.22070.159-0.75340.01660.68040.03910.02560.67590.22430.588214.48563.053331.2142
24.1915-0.8552-0.34461.21320.30711.20820.0199-0.25790.28980.0175-0.1046-0.05730.0988-0.28510.00040.47740.08880.05990.56560.08410.498114.48817.864217.9682
31.3694-0.1054-0.00990.5620.53170.69780.46090.8171-0.7845-1.1228-0.36460.18210.5591-0.915-0.00550.99990.0187-0.0470.7333-0.03530.75438.4647-0.17380.1005
42.54331.2439-0.24161.9771.69652.33420.02210.1503-0.0707-0.4934-0.02750.03060.4523-0.34950.00020.53750.05390.03220.47270.07790.49212.09194.43126.9088
53.07970.29551.43022.49772.18272.22330.106-0.3151-0.22570.03250.03-0.69810.21020.16710.00050.4470.11080.05850.48230.1130.548620.279810.388116.8899
60.09480.07510.09390.18410.25440.2461-0.57580.52260.07430.00520.95680.56770.12251.75470.0110.73220.01180.00310.86190.06510.650922.975410.5078-33.034
73.9292-0.3918-0.24631.78150.0660.80430.13440.12560.01340.0285-0.3133-0.18230.21020.4223-0.00290.5524-0.08790.01430.4914-0.02230.374521.724114.9102-15.1422
83.1354-1.55390.03412.2203-1.45531.0999-0.01580.0387-0.34980.2030.1463-0.06310.27470.27860.00220.5522-0.06990.00230.4599-0.06550.453522.30256.2923-10.8817
92.04940.14630.53461.785-1.25330.98580.36910.2726-0.1815-0.1025-0.32520.60540.2192-0.16090.00080.4509-0.0834-0.00570.5065-0.10730.556914.02414.5147-19.8975
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 234 through 253 )
2X-RAY DIFFRACTION2chain 'A' and (resid 254 through 288 )
3X-RAY DIFFRACTION3chain 'A' and (resid 289 through 305 )
4X-RAY DIFFRACTION4chain 'A' and (resid 306 through 334 )
5X-RAY DIFFRACTION5chain 'A' and (resid 335 through 378 )
6X-RAY DIFFRACTION6chain 'B' and (resid 239 through 253 )
7X-RAY DIFFRACTION7chain 'B' and (resid 254 through 304 )
8X-RAY DIFFRACTION8chain 'B' and (resid 305 through 334 )
9X-RAY DIFFRACTION9chain 'B' and (resid 335 through 378 )

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