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- PDB-6p6g: Co-crystal Structure of human SMYD3 with Isoxazole Amides Inhibitors -

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Basic information

Entry
Database: PDB / ID: 6p6g
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
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 / metal ion binding / 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 / 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-LUP / S-ADENOSYL-L-HOMOCYSTEINE / Histone-lysine N-methyltransferase SMYD3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.59 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 3, 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)50,96911
Polymers49,5431
Non-polymers1,42610
Water7,044391
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)61.433, 66.636, 107.340
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, 401 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 / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE / S-Adenosyl-L-homocysteine


Type: L-peptide linking / Mass: 384.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N6O5S
#6: Chemical ChemComp-LUP / 5-cyclopropyl-N-{1-[({trans-4-[(4,4,4-trifluorobutyl)amino]cyclohexyl}methyl)sulfonyl]piperidin-4-yl}-1,2-oxazole-3-carboxamide


Mass: 520.609 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H35F3N4O4S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 391 / Source method: isolated from a natural source / Formula: H2O

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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: 2.22 Å3/Da / Density % sol: 44.53 %
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: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.07805 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / 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: 1.59→66.64 Å / Num. obs: 60184 / % possible obs: 99.6 % / Redundancy: 6.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.029 / Rrim(I) all: 0.077 / Net I/σ(I): 15 / Num. measured all: 413998
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.59-1.675.50.57284540.8710.2630.63297.6
1.66-1.710.0371000.9990.0150.04

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Processing

Software
NameVersionClassification
Aimless0.5.27data scaling
PHENIX(1.14_3260)refinement
PDB_EXTRACT3.24data extraction
DENZOdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.59→56.614 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 20.9
RfactorNum. reflection% reflection
Rfree0.2002 5654 4.94 %
Rwork0.1723 --
obs0.1737 114482 99.32 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 89.92 Å2 / Biso mean: 23.7103 Å2 / Biso min: 9.08 Å2
Refinement stepCycle: final / Resolution: 1.59→56.614 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3326 0 86 396 3808
Biso mean--22.98 31.1 -
Num. residues----426
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 (%)
1.5862-1.60420.31461540.28493291344591
1.6042-1.62310.32251690.27353472364194
1.6231-1.64290.34141840.26053583376797
1.6429-1.66370.24551670.233836963863100
1.6637-1.68560.22871830.224136093792100
1.6856-1.70870.2341990.215136873886100
1.7087-1.73310.23262000.201635903790100
1.7331-1.7590.25282000.192536663866100
1.759-1.78650.21641880.188736133801100
1.7865-1.81570.2341950.190336903885100
1.8157-1.84710.2092080.18536223830100
1.8471-1.88060.19951660.18336533819100
1.8806-1.91680.20461490.177736973846100
1.9168-1.95590.20472060.181636643870100
1.9559-1.99850.2581880.190436323820100
1.9985-2.0450.25591960.17836513847100
2.045-2.09610.20722090.183836393848100
2.0961-2.15280.22581680.176836573825100
2.1528-2.21610.2151940.176636623856100
2.2161-2.28770.22371890.171236453834100
2.2877-2.36940.22251860.172336503836100
2.3694-2.46430.18471940.173936403834100
2.4643-2.57650.20661780.169936683846100
2.5765-2.71230.20152120.173836153827100
2.7123-2.88220.17741700.171136833853100
2.8822-3.10470.20921960.167536263822100
3.1047-3.41710.18791870.159636663853100
3.4171-3.91150.17121750.145736593834100
3.9115-4.92770.14922070.135536183825100
4.9277-56.650.18852370.1743584382199

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