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- PDB-6paf: Co-crystal Structure of human SMYD3 with Isoxazole Amides Inhibitors -

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Basic information

Entry
Database: PDB / ID: 6paf
TitleCo-crystal Structure of human SMYD3 with Isoxazole Amides Inhibitors
ComponentsHistone-lysine N-methyltransferase SMYD3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / methyltransferase / oncology / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


histone H3K36 dimethyltransferase activity / histone H4 methyltransferase activity / [histone H3]-lysine4 N-trimethyltransferase / myotube cell development / histone H3K4 trimethyltransferase activity / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / RNA polymerase II complex binding / cellular response to dexamethasone stimulus / establishment of protein localization / PKMTs methylate histone lysines ...histone H3K36 dimethyltransferase activity / histone H4 methyltransferase activity / [histone H3]-lysine4 N-trimethyltransferase / myotube cell development / histone H3K4 trimethyltransferase activity / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / RNA polymerase II complex binding / cellular response to dexamethasone stimulus / establishment of protein localization / PKMTs methylate histone lysines / nucleosome assembly / methylation / RNA polymerase II cis-regulatory region sequence-specific DNA binding / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Histone-lysine N-methyltransferase Smyd3 / SMYD3, SET domain / Histone-lysine N-methyltransferase (EC 2.1.1.43) family profile. / : / MYND finger / Zinc finger MYND-type signature. / Zinc finger, MYND-type / Zinc finger MYND-type profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain ...Histone-lysine N-methyltransferase Smyd3 / SMYD3, SET domain / Histone-lysine N-methyltransferase (EC 2.1.1.43) family profile. / : / MYND finger / Zinc finger MYND-type signature. / Zinc finger, MYND-type / Zinc finger MYND-type profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain superfamily / SET domain profile. / SET domain / Tetratricopeptide-like helical domain superfamily
Similarity search - Domain/homology
Chem-O6A / S-ADENOSYLMETHIONINE / Histone-lysine N-methyltransferase SMYD3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.241 Å
AuthorsElkins, P.A. / Wang, L.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors.
Authors: Su, D.S. / Qu, J. / Schulz, M. / Blackledge, C.W. / Yu, H. / Zeng, J. / Burgess, J. / Reif, A. / Stern, M. / Nagarajan, R. / Pappalardi, M.B. / Wong, K. / Graves, A.P. / Bonnette, W. / Wang, ...Authors: Su, D.S. / Qu, J. / Schulz, M. / Blackledge, C.W. / Yu, H. / Zeng, J. / Burgess, J. / Reif, A. / Stern, M. / Nagarajan, R. / Pappalardi, M.B. / Wong, K. / Graves, A.P. / Bonnette, W. / Wang, L. / Elkins, P. / Knapp-Reed, B. / Carson, J.D. / McHugh, C. / Mohammad, H. / Kruger, R. / Luengo, J. / Heerding, D.A. / Creasy, C.L.
History
DepositionJun 11, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 15, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 11, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone-lysine N-methyltransferase SMYD3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,77410
Polymers49,5431
Non-polymers1,2329
Water8,773487
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)60.971, 65.991, 106.544
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Histone-lysine N-methyltransferase SMYD3 / SET and MYND domain-containing protein 3 / Zinc finger MYND domain-containing protein 1


Mass: 49542.520 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SMYD3, ZMYND1, ZNFN3A1 / Cell line (production host): Sf9 / Production host: unidentified baculovirus
References: UniProt: Q9H7B4, histone-lysine N-methyltransferase

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Non-polymers , 6 types, 496 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#6: Chemical ChemComp-O6A / N-(1-{[4-(aminomethyl)phenyl]sulfonyl}piperidin-4-yl)-5-cyclopropyl-1,2-oxazole-3-carboxamide


Mass: 404.483 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24N4O4S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 487 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.16 Å3/Da / Density % sol: 43.14 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: Sitting Drop, Linbro tray, room temp, reservoir is 10% PEG 3350, 0.2M MgOAc , protein:reservoir is 1:1, streak seed soaking: 2ul 20%PEG 3350, 0.4M MgOAc added to 2ul protein, mix and add 0. ...Details: Sitting Drop, Linbro tray, room temp, reservoir is 10% PEG 3350, 0.2M MgOAc , protein:reservoir is 1:1, streak seed soaking: 2ul 20%PEG 3350, 0.4M MgOAc added to 2ul protein, mix and add 0.3ul to drop, store at 295

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Data collection

DiffractionMean temperature: 295 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.07805 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 5, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07805 Å / Relative weight: 1
ReflectionResolution: 1.24→50 Å / Num. obs: 118748 / % possible obs: 97 % / Redundancy: 4.8 % / Rmerge(I) obs: 0.072 / Rpim(I) all: 0.036 / Rrim(I) all: 0.081 / Χ2: 1.054 / Net I/σ(I): 12.4 / Num. measured all: 571090
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.24-1.284.80.417109160.8750.2070.4681.00390.5
1.28-1.344.90.334116840.9120.1650.3741.09196.3
1.34-1.44.90.257117120.9470.1260.2881.06196.8
1.4-1.474.90.198118190.9670.0970.2211.06397.3
1.47-1.564.90.156118670.9790.0760.1741.0697.7
1.56-1.684.90.12119580.9860.0580.1341.06298.2
1.68-1.854.90.093120320.990.0450.1031.05598.5
1.85-2.124.80.074121300.9930.0370.0831.06598.9
2.12-2.674.70.061122340.9940.030.0681.03298.9
2.67-504.40.054123960.9950.0280.0611.04197.1

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Processing

Software
NameVersionClassification
PHENIX1.16-3549refinement
XDSdata reduction
Aimlessdata scaling
PDB_EXTRACT3.25data extraction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5HI7

5hi7


Resolution: 1.241→32.995 Å / SU ML: 0.11 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 18.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1875 8461 7.13 %RANDOM
Rwork0.1718 110230 --
obs0.1729 118691 97.46 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 59.36 Å2 / Biso mean: 17.3398 Å2 / Biso min: 5.91 Å2
Refinement stepCycle: final / Resolution: 1.241→32.995 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3311 0 72 492 3875
Biso mean--12.13 25.78 -
Num. residues----423
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.2412-1.25530.25882620.2439338592
1.2553-1.27010.22492800.2252360596
1.2701-1.28560.22732620.2194356996
1.2856-1.30190.2352720.2142359296
1.3019-1.3190.23012860.2058360296
1.319-1.33710.22632700.2069359597
1.3371-1.35620.22542750.1996362097
1.3562-1.37640.22232600.1984362897
1.3764-1.39790.21562910.1888359497
1.3979-1.42080.19592540.1935368697
1.4208-1.44530.20722680.1868362297
1.4453-1.47160.21472790.1826365398
1.4716-1.49990.19332940.1751365097
1.4999-1.53050.19252830.1721367598
1.5305-1.56380.18812670.1731364798
1.5638-1.60020.17722850.1668368498
1.6002-1.64020.20972780.1689369598
1.6402-1.68450.18222790.1664369898
1.6845-1.73410.18333180.1623367699
1.7341-1.79010.19033110.1686368299
1.7901-1.85410.20353100.1659367799
1.8541-1.92830.17332730.1689374399
1.9283-2.0160.17992770.1723376899
2.016-2.12230.17623220.1643368699
2.1223-2.25520.17482680.1597378299
2.2552-2.42930.18012350.1645382699
2.4293-2.67370.17722980.1721376399
2.6737-3.06030.1842920.1775378898
3.0603-3.85480.18252910.1629382098
3.8548-500.1733210.1573381995
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)
10.550.0175-0.25841.0768-0.06312.42830.0238-0.10840.0550.30590.07840.118-0.20920.234-0.07310.1363-0.00670.04880.1208-0.00160.14719.882-3.382-4.547
21.0442-0.4981-0.18971.1980.27831.3147-0.0559-0.1709-0.04410.20150.06420.05170.0979-0.015-0.01050.0746-0.00190.01650.09770.01220.070114.475-17.588-5.615
30.67030.4759-0.27631.0335-0.17170.40960.0758-0.0590.09520.1143-0.02870.0748-0.09620.0272-0.02850.08390.00170.01230.06910.00780.065222.4827.707-18.717
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 3:93 )A3 - 93
2X-RAY DIFFRACTION2( CHAIN A AND RESID 96:186 )A96 - 186
3X-RAY DIFFRACTION3( CHAIN A AND RESID 187:428 )A187 - 428

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