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- PDB-6p7z: Co-crystal Structure of human SMYD3 with Isoxazole Amides Inhibitors -

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Basic information

Entry
Database: PDB / ID: 6p7z
TitleCo-crystal Structure of human SMYD3 with Isoxazole Amides Inhibitors
ComponentsHistone-lysine N-methyltransferase SMYD3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / methyltransferase / oncology / inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex / TRANSFERASE
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 / positive regulation of peptidyl-serine phosphorylation / methylation / RNA polymerase II cis-regulatory region sequence-specific DNA binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / metal ion binding / 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 / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / 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 / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / Tetratricopeptide-like helical domain superfamily
Similarity search - Domain/homology
Chem-O41 / S-ADENOSYLMETHIONINE / Histone-lysine N-methyltransferase SMYD3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.19 Å
AuthorsElkins, P.A. / Bonnette, W.G.
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 6, 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 1.2Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)50,4998
Polymers49,5431
Non-polymers9577
Water9,908550
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)61.140, 66.179, 107.330
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 , 5 types, 557 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-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#5: Chemical ChemComp-O41 / 5-cyclopropyl-N-[1-(methylsulfonyl)piperidin-4-yl]-1,2-oxazole-3-carboxamide


Mass: 313.373 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H19N3O4S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 550 / 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: 2.19 Å3/Da / Density % sol: 43.87 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: Sitting drop, room temp, reservoir is 20%PEG 3350, 0.2M MgOAc protein at 5mg/ml ratio to reservoir is 1:1, seed Soaking: 0.1ul of 200mM compound in DMSO added to drop for 72 hours before harvest

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 1 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Oct 10, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.19→50 Å / Num. obs: 138790 / % possible obs: 99 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.07 / Χ2: 1.001 / Net I/σ(I): 9.2 / Num. measured all: 501496
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.19-1.233.40.46133960.985196.8
1.23-1.283.60.384138490.998199.9
1.28-1.343.60.311138851.0071100
1.34-1.413.60.237139081.0021100
1.41-1.53.60.171139041.022199.9
1.5-1.623.70.118138780.992199.3
1.62-1.783.70.09138071.007198.8
1.78-2.033.70.078138930.996199
2.03-2.563.60.06140531.008199.3
2.56-503.60.043142170.993197.5

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Processing

Software
NameVersionClassification
PHENIX(1.15.2_3472)refinement
DENZOdata reduction
HKL-2000data scaling
PDB_EXTRACT3.25data extraction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.19→31.621 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 19.46 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1981 6967 5.02 %
Rwork0.1809 131760 -
obs0.1818 138727 99.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 66.55 Å2 / Biso mean: 15.2884 Å2 / Biso min: 5.19 Å2
Refinement stepCycle: final / Resolution: 1.19→31.621 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3351 0 53 560 3964
Biso mean--17.6 24.57 -
Num. residues----425
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.19-1.20350.27482250.26194207443296
1.2035-1.21770.242000.251343994599100
1.2177-1.23250.29362300.237243574587100
1.2325-1.24810.23472320.231344224654100
1.2481-1.26450.252570.235543194576100
1.2645-1.28180.24892350.221843454580100
1.2818-1.30020.23492170.221644504667100
1.3002-1.31960.21172200.216543324552100
1.3196-1.34020.21512190.207244254644100
1.3402-1.36220.22562450.208944024647100
1.3622-1.38570.22442200.204144104630100
1.3857-1.41080.23482260.200943644590100
1.4108-1.4380.22242540.197643784632100
1.438-1.46730.20592110.196344244635100
1.4673-1.49920.20962360.187343804616100
1.4992-1.53410.1762420.18274381462399
1.5341-1.57250.18252390.17774371461099
1.5725-1.6150.20212200.16984385460599
1.615-1.66250.19622270.17434351457899
1.6625-1.71620.17842470.17424337458499
1.7162-1.77750.20512320.17264379461199
1.7775-1.84870.19252230.17724392461599
1.8487-1.93280.21422470.17954372461999
1.9328-2.03470.19862210.17764415463699
2.0347-2.16210.18742450.17054409465499
2.1621-2.3290.18312670.17144397466499
2.329-2.56330.17042120.17244495470799
2.5633-2.9340.22022320.18154473470599
2.934-3.69560.17142340.16444504473899
3.6956-31.6320.17922520.15434485473795
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)
10.3850.0531-0.11770.4839-0.05481.11940.0117-0.07120.02810.14650.03580.0467-0.09570.099-0.03740.08840.00550.01910.0895-0.00120.092810.023-3.18-4.522
20.5748-0.3-0.12350.68360.1730.6376-0.0428-0.1016-0.01670.13570.05470.01320.07020.0018-0.0130.0810.00440.00920.09870.0080.076314.663-17.561-5.274
30.48230.3391-0.22910.5846-0.18780.3630.066-0.0350.06810.0839-0.02460.0392-0.10210.02-0.02640.0836-0.00150.01110.06060.00580.062822.5287.712-18.917
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 95:186 )A95 - 186
3X-RAY DIFFRACTION3( CHAIN A AND RESID 187:427 )A187 - 427

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