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- PDB-5arf: SMYD2 in complex with small molecule inhibitor compound-2 -

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Basic information

Entry
Database: PDB / ID: 5arf
TitleSMYD2 in complex with small molecule inhibitor compound-2
ComponentsN-LYSINE METHYLTRANSFERASE SMYD2
KeywordsTRANSFERASE / METHYLTRANSFERASE / SET DOMAIN / SMALL MOLECULE INHIBITOR / SGC PROBE / DRUG TARGET
Function / homology
Function and homology information


lysine N-methyltransferase activity / [histone H3]-lysine4 N-trimethyltransferase / peptidyl-lysine monomethylation / peptidyl-lysine dimethylation / histone H3K4 trimethyltransferase activity / histone H3K36 methyltransferase activity / protein-lysine N-methyltransferase activity / histone H3 methyltransferase activity / regulation of DNA damage response, signal transduction by p53 class mediator / RNA polymerase II complex binding ...lysine N-methyltransferase activity / [histone H3]-lysine4 N-trimethyltransferase / peptidyl-lysine monomethylation / peptidyl-lysine dimethylation / histone H3K4 trimethyltransferase activity / histone H3K36 methyltransferase activity / protein-lysine N-methyltransferase activity / histone H3 methyltransferase activity / regulation of DNA damage response, signal transduction by p53 class mediator / RNA polymerase II complex binding / Transferases; Transferring one-carbon groups; Methyltransferases / regulation of signal transduction by p53 class mediator / Regulation of TP53 Activity through Methylation / PKMTs methylate histone lysines / p53 binding / heart development / negative regulation of cell population proliferation / negative regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / metal ion binding / cytoplasm / cytosol
Similarity search - Function
SMYD2, SET domain / MYND finger / Zinc finger, MYND-type / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. / Beta-clip-like / SET domain / Tetratricopeptide repeat domain / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily ...SMYD2, SET domain / MYND finger / Zinc finger, MYND-type / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. / Beta-clip-like / SET domain / Tetratricopeptide repeat domain / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / Beta Complex / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Tetratricopeptide-like helical domain superfamily / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-I9H / S-ADENOSYLMETHIONINE / N-lysine methyltransferase SMYD2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsHillig, R.C. / Badock, V. / Barak, N. / Stellfeld, T. / Eggert, E. / ter Laak, A. / Weiske, J. / Christ, C.D. / Koehr, S. / Stoeckigt, D. ...Hillig, R.C. / Badock, V. / Barak, N. / Stellfeld, T. / Eggert, E. / ter Laak, A. / Weiske, J. / Christ, C.D. / Koehr, S. / Stoeckigt, D. / Mowat, J. / Mueller, T. / Fernandez-Montalvan, A.E. / Hartung, I.V. / Stresemann, C. / Brumby, T. / Weinmann, H.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (Bay-598) for the Protein Lysine Methyltransferase Smyd2.
Authors: Eggert, E. / Hillig, R.C. / Kohr, S. / Stockigt, D. / Weiske, J. / Barak, N. / Mowat, J. / Brumby, T. / Christ, C.D. / Ter Laak, A. / Lang, T. / Fernandez-Montalvan, A.E. / Badock, V. / ...Authors: Eggert, E. / Hillig, R.C. / Kohr, S. / Stockigt, D. / Weiske, J. / Barak, N. / Mowat, J. / Brumby, T. / Christ, C.D. / Ter Laak, A. / Lang, T. / Fernandez-Montalvan, A.E. / Badock, V. / Weinmann, H. / Hartung, I.V. / Barsyte-Lovejoy, D. / Szewczyk, M. / Kennedy, S. / Li, F. / Vedadi, M. / Brown, P.J. / Santhakumar, V. / Arrowsmith, C.H. / Stellfeld, T. / Stresemann, C.
History
DepositionSep 24, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 27, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 8, 2016Group: Database references
Revision 1.2Sep 13, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.type
Revision 1.3Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_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 / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_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 SMYD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,7726
Polymers49,6861
Non-polymers1,0865
Water2,288127
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)130.493, 51.759, 69.568
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 SMYD2


Mass: 49685.957 Da / Num. of mol.: 1 / Fragment: SET DOMAIN, UNP RESIDUES 2-433
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: Q9NRG4, Transferases; Transferring one-carbon groups; Methyltransferases, histone-lysine N-methyltransferase
#2: Chemical ChemComp-I9H / N-[3-(4-CHLOROPHENYL)-1-{N'-CYANO-N-[3-(DIFLUOROMETHOXY)PHENYL]CARBAMIMIDOYL}-4,5-DIHYDRO-1H- PYRAZOL-4-YL]-N-ETHYL-2-HYDROXYACETAMIDE


Mass: 490.890 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21ClF2N6O3
#3: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 127 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsN-[3-(4-CHLOROPHENYL)-1-{N'-CYANO-N-[3-(DIFLUOROMETHOXY)PHENYL] CARBAMIMIDOYL}-4,5-DIHYDRO-1H- ...N-[3-(4-CHLOROPHENYL)-1-{N'-CYANO-N-[3-(DIFLUOROMETHOXY)PHENYL] CARBAMIMIDOYL}-4,5-DIHYDRO-1H-PYRAZOL-4-YL]-N-ETHYL-2- HYDROXYACETAMIDE

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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: 2.41 Å3/Da / Density % sol: 49 % / Description: NONE
Crystal growpH: 7
Details: SMYD2 CO-CRYSTALLIZED WITH 2 MMOL SAM. RESERVOIR 23% PEG 3350, 100 MMOL HEPES PH 7.0. CO-COMPLEX WITH INHIBITOR FORMED BY SOAKING SMYD2-SAM CRYSTALS WITH 5 MILLIMOLAR COMPOUND-2 FOR 1 HOUR. ...Details: SMYD2 CO-CRYSTALLIZED WITH 2 MMOL SAM. RESERVOIR 23% PEG 3350, 100 MMOL HEPES PH 7.0. CO-COMPLEX WITH INHIBITOR FORMED BY SOAKING SMYD2-SAM CRYSTALS WITH 5 MILLIMOLAR COMPOUND-2 FOR 1 HOUR. CRYO WITH ADDITIONAL 20% GLYCEROL AND 1 MMOL COMPOUND-2.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.918409
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 6, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918409 Å / Relative weight: 1
ReflectionResolution: 1.92→48.11 Å / Num. obs: 36156 / % possible obs: 97.9 % / Observed criterion σ(I): 0 / Redundancy: 3.69 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 12.83
Reflection shellResolution: 1.92→2.03 Å / Rmerge(I) obs: 0.7 / Mean I/σ(I) obs: 2.3 / % possible all: 97.4

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3TG5

3tg5


Resolution: 1.92→47.59 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.883 / Cross valid method: THROUGHOUT / ESU R: 0.215 / ESU R Free: 0.191 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. B FACTORS WITH TLS ADDED.
RfactorNum. reflection% reflectionSelection details
Rfree0.30052 1808 5 %RANDOM
Rwork0.25747 ---
obs0.25958 34348 97.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 52.97 Å2
Baniso -1Baniso -2Baniso -3
1--0.22 Å20 Å20 Å2
2--0.32 Å20 Å2
3----0.1 Å2
Refinement stepCycle: LAST / Resolution: 1.92→47.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3419 0 64 127 3610
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0193563
X-RAY DIFFRACTIONr_bond_other_d00.023364
X-RAY DIFFRACTIONr_angle_refined_deg1.9861.9854807
X-RAY DIFFRACTIONr_angle_other_deg3.6313.0017755
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4385424
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.70124.217166
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.01115642
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6851520
X-RAY DIFFRACTIONr_chiral_restr0.1110.2510
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0213969
X-RAY DIFFRACTIONr_gen_planes_other0.0190.02804
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2550.4431702
X-RAY DIFFRACTIONr_mcbond_other1.2530.4441702
X-RAY DIFFRACTIONr_mcangle_it1.8540.9832124
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.3360.6731861
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.918→1.968 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 127 -
Rwork0.325 2418 -
obs--95.86 %
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)
14.40540.013-3.82280.97820.86578.304-0.37050.84970.1350.11420.4131-0.06790.9678-0.4421-0.04260.2797-0.0978-0.03260.36250.00870.090119.522-14.103-7.727
25.2749-0.2432-3.28380.98781.01637.79910.25380.86860.7892-0.15890.06510.1948-0.4007-1.702-0.31880.20320.0397-0.00590.47740.16670.2751.742-4.1058.261
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A6 - 271
2X-RAY DIFFRACTION2A272 - 430

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