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- PDB-6boz: Structure of human SETD8 in complex with covalent inhibitor MS4138 -

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Basic information

Entry
Database: PDB / ID: 6boz
TitleStructure of human SETD8 in complex with covalent inhibitor MS4138
ComponentsN-lysine methyltransferase KMT5A
KeywordsTRANSFERASE/TRANSFERASE inhibitor / protein-small molecule inhibitor complex / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


lysine N-methyltransferase activity / [histone H4]-lysine20 N-methyltransferase / histone H4K20 monomethyltransferase activity / histone H4K20 methyltransferase activity / histone H4 methyltransferase activity / polytene chromosome / peptidyl-lysine monomethylation / protein-lysine N-methyltransferase activity / mitotic chromosome condensation / regulation of DNA damage response, signal transduction by p53 class mediator ...lysine N-methyltransferase activity / [histone H4]-lysine20 N-methyltransferase / histone H4K20 monomethyltransferase activity / histone H4K20 methyltransferase activity / histone H4 methyltransferase activity / polytene chromosome / peptidyl-lysine monomethylation / protein-lysine N-methyltransferase activity / mitotic chromosome condensation / 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 / Condensation of Prophase Chromosomes / regulation of signal transduction by p53 class mediator / Regulation of TP53 Activity through Methylation / PKMTs methylate histone lysines / transcription corepressor activity / cell division / negative regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / 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. / : / : / Beta-clip-like / SET domain / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain superfamily / SET domain profile. ...Class V SAM-dependent methyltransferases / Histone-lysine N-methyltransferase (EC 2.1.1.43) family profile. / : / : / Beta-clip-like / SET domain / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain superfamily / SET domain profile. / SET domain / Beta Complex / Mainly Beta
Similarity search - Domain/homology
Chem-E1J / N-lysine methyltransferase KMT5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.4 Å
AuthorsBabault, N. / Anqi, M. / Jin, J.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM122749 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA218600 United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)R01HD088626 United States
CitationJournal: Elife / Year: 2019
Title: The dynamic conformational landscape of the protein methyltransferase SETD8.
Authors: Chen, S. / Wiewiora, R.P. / Meng, F. / Babault, N. / Ma, A. / Yu, W. / Qian, K. / Hu, H. / Zou, H. / Wang, J. / Fan, S. / Blum, G. / Pittella-Silva, F. / Beauchamp, K.A. / Tempel, W. / ...Authors: Chen, S. / Wiewiora, R.P. / Meng, F. / Babault, N. / Ma, A. / Yu, W. / Qian, K. / Hu, H. / Zou, H. / Wang, J. / Fan, S. / Blum, G. / Pittella-Silva, F. / Beauchamp, K.A. / Tempel, W. / Jiang, H. / Chen, K. / Skene, R.J. / Zheng, Y.G. / Brown, P.J. / Jin, J. / Luo, C. / Chodera, J.D. / Luo, M.
History
DepositionNov 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2019Provider: repository / Type: Initial release
Revision 1.1May 29, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Nov 13, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)44,3885
Polymers43,4972
Non-polymers8913
Water1,33374
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2860 Å2
ΔGint-10 kcal/mol
Surface area13990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)31.560, 68.060, 125.900
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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/SET07 / SET domain-containing protein 8


Mass: 21748.379 Da / Num. of mol.: 2 / Fragment: human SETD8 catalytic domain (232-393) / Mutation: C343S
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 (E. coli) / Strain (production host): BL21 (DE3) codon plus RIL
References: UniProt: Q9NQR1, Transferases; Transferring one-carbon groups; Methyltransferases, histone-lysine N-methyltransferase
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: 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.: 2 / Source method: obtained synthetically / Formula: C21H30N6O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 74 / Source method: isolated from a natural source / Formula: H2O
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: 1.55 Å3/Da / Density % sol: 20.87 % / Mosaicity: 0.47 °
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 7
Details: 20% (w/v) PEG 6,000, 0.2 M MgCl, 0.1 M HEPES (pH 7.0)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.4→62.95 Å / Num. all: 11209 / Num. obs: 11209 / % possible obs: 99.5 % / Redundancy: 3.6 % / Biso Wilson estimate: 30.01 Å2 / Rpim(I) all: 0.066 / Rrim(I) all: 0.129 / Rsym value: 0.11 / Net I/av σ(I): 4.8 / Net I/σ(I): 8.2 / Num. measured all: 39948
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
2.4-2.5330.3611.815500.2420.4370.36197.8
2.53-2.683.40.2772.415270.1740.3290.27799.5
2.68-2.873.80.2083.214360.1230.2420.20899.8
2.87-3.13.80.1444.713310.0840.1670.144100
3.1-3.393.80.1046.112340.0610.1210.104100
3.39-3.793.80.0916.311350.0540.1060.091100
3.79-4.383.80.0816.910040.0470.0940.08199.9
4.38-5.373.60.0836.78740.0490.0970.08399.9
5.37-7.593.40.0975.36920.060.1140.09799.9
7.59-68.063.10.0855.34260.0550.1020.08599.6

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
SCALA3.3.22data scaling
PDB_EXTRACT3.22data extraction
PHASERphasing
RefinementResolution: 2.4→62.95 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.48
RfactorNum. reflection% reflection
Rfree0.2419 574 5.14 %
Rwork0.1787 --
obs0.182 11165 99.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 107.65 Å2 / Biso mean: 38.9112 Å2 / Biso min: 9.9 Å2
Refinement stepCycle: final / Resolution: 2.4→62.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2161 0 64 74 2299
Biso mean--20.03 29.66 -
Num. residues----273
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072264
X-RAY DIFFRACTIONf_angle_d0.9163036
X-RAY DIFFRACTIONf_chiral_restr0.051319
X-RAY DIFFRACTIONf_plane_restr0.004390
X-RAY DIFFRACTIONf_dihedral_angle_d10.3851357
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4-2.64150.29341340.21782574270898
2.6415-3.02380.26091410.213825802721100
3.0238-3.80960.26241440.165726532797100
3.8096-62.97160.20591550.162227842939100
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)
19.5085-1.4986-1.94978.86711.69794.3479-0.32490.7591-1.7566-0.5497-0.34460.55670.03650.19250.53351.11540.44870.10930.6495-0.15270.6544-1.968-16.51522.062
26.98882.08691.31686.80262.21868.61170.13750.35940.3379-0.92470.1941-0.0897-0.32020.1001-0.34050.2423-0.08690.04490.2569-0.00370.2555-4.8083.99722.878
36.39640.751-0.19855.5984-0.55225.52260.54250.4388-0.3441-0.6055-0.27310.06270.9244-0.3992-0.13750.21990.04490.02960.2641-0.0350.1746-9.067-7.57323.193
45.1431-1.9660.33067.03074.08536.23590.1407-0.5109-0.26860.08550.4046-0.61330.04680.1752-0.49520.13560.0339-0.03520.23390.00180.22125.111-9.68745.878
55.9142-3.1692-1.37631.8824-0.26367.3586-0.1492-0.0398-0.08380.26680.2041-0.02750.4519-0.1061-0.10190.14790.0016-0.03580.286-0.02740.1779-1.428-7.79342.789
65.5682.74744.31113.78041.01093.8905-0.12550.86010.06-0.10730.3319-0.81490.35531.34480.14640.16250.0858-0.07340.4315-0.01440.41964.197-2.14931.128
74.2458-1.53342.39149.3781-1.55022.93620.0656-0.4924-0.252-0.14810.12720.96280.2502-0.1915-0.18160.2229-0.0638-0.01390.27510.05210.1683-10.104-5.91731.176
81.01440.1021-1.2123.8672-1.15471.723-0.05010.2490.00660.0420.17480.15510.2156-0.0227-0.12290.25860.0067-0.1060.20050.00420.2167-10.659-7.64926.032
92.21351.6277-2.71741.9968-2.19163.2398-0.2173-0.5543-0.267-0.5308-0.42240.87460.7883-0.18220.37990.3339-0.09580.00420.3614-0.04250.4962-18.008-8.91535.047
102.5337-1.0898-3.26690.87671.2176.86610.2607-0.12540.04750.50060.12390.1040.10640.17020.58561.5059-0.5410.80670.7277-0.3270.3934-6.219-4.52873.087
114.9911.21120.52072.1553-3.4347.6698-0.04240.05420.16080.25220.1365-0.04560.0017-0.8919-0.09650.34060.02210.03550.3707-0.08940.3123-5.65212.37164.74
124.162-0.07180.82625.21831.25886.69260.2335-0.12640.18990.7855-0.301-0.0130.00790.08490.10970.1918-0.04250.05180.2691-0.06990.174-0.6117.9363.867
135.80292.1907-0.51212.82032.15824.05160.08150.35760.3457-0.2366-0.00570.5561-0.1883-0.7548-0.13040.1358-0.01150.00190.29150.00670.2634-12.744-4.14446.448
142.5013-0.01810.68027.4468-0.55667.23370.07910.069-0.63640.3524-0.1673-0.02240.98360.55230.15390.34960.02540.0090.2914-0.00420.257-5.775-11.21754.016
154.20342.16221.21067.9273-0.5515.24320.3014-0.07310.05820.503-0.2360.45350.0566-0.1651-0.07070.2427-0.00070.03470.2106-0.07130.2128-3.6192.31358.683
160.8988-0.13270.47866.55861.342.2410.2109-0.22240.11010.4728-0.2572-0.34130.1702-0.48110.03090.2586-0.04190.00920.25340.0160.18671.3182.13164.663
172.35331.34190.50360.82491.00648.0873-0.04920.3345-1.0940.11080.6181-1.26791.32510.9558-0.07320.29370.09230.04620.2773-0.11110.51344.3530.4555.605
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 246:253 )A246 - 253
2X-RAY DIFFRACTION2( CHAIN A AND RESID 254:273 )A254 - 273
3X-RAY DIFFRACTION3( CHAIN A AND RESID 274:288 )A274 - 288
4X-RAY DIFFRACTION4( CHAIN A AND RESID 289:302 )A289 - 302
5X-RAY DIFFRACTION5( CHAIN A AND RESID 303:326 )A303 - 326
6X-RAY DIFFRACTION6( CHAIN A AND RESID 327:334 )A327 - 334
7X-RAY DIFFRACTION7( CHAIN A AND RESID 335:353 )A335 - 353
8X-RAY DIFFRACTION8( CHAIN A AND RESID 354:373 )A354 - 373
9X-RAY DIFFRACTION9( CHAIN A AND RESID 374:384 )A374 - 384
10X-RAY DIFFRACTION10( CHAIN B AND RESID 246:253 )B246 - 253
11X-RAY DIFFRACTION11( CHAIN B AND RESID 254:264 )B254 - 264
12X-RAY DIFFRACTION12( CHAIN B AND RESID 265:288 )B265 - 288
13X-RAY DIFFRACTION13( CHAIN B AND RESID 289:312 )B289 - 312
14X-RAY DIFFRACTION14( CHAIN B AND RESID 313:326 )B313 - 326
15X-RAY DIFFRACTION15( CHAIN B AND RESID 327:353 )B327 - 353
16X-RAY DIFFRACTION16( CHAIN B AND RESID 354:373 )B354 - 373
17X-RAY DIFFRACTION17( CHAIN B AND RESID 374:379 )B374 - 379

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