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- PDB-3k5k: Discovery of a 2,4-Diamino-7-aminoalkoxy-quinazoline as a Potent ... -

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Basic information

Entry
Database: PDB / ID: 3k5k
TitleDiscovery of a 2,4-Diamino-7-aminoalkoxy-quinazoline as a Potent Inhibitor of Histone Lysine Methyltransferase, G9a
ComponentsHistone-lysine N-methyltransferase, H3 lysine-9 specific 3
KeywordsTRANSFERASE / Histone Lysine Methyltransferase / G9A / ANK repeat / Chromatin regulator / Metal-binding / Methyltransferase / Nucleus / Phosphoprotein / S-adenosyl-L-methionine / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


regulation of protein modification process / histone H3K56 methyltransferase activity / phenotypic switching / neuron fate specification / [histone H3]-lysine9 N-methyltransferase / peptidyl-lysine dimethylation / histone H3K27 methyltransferase activity / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / synaptonemal complex assembly ...regulation of protein modification process / histone H3K56 methyltransferase activity / phenotypic switching / neuron fate specification / [histone H3]-lysine9 N-methyltransferase / peptidyl-lysine dimethylation / histone H3K27 methyltransferase activity / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / synaptonemal complex assembly / negative regulation of autophagosome assembly / oocyte development / protein-lysine N-methyltransferase activity / C2H2 zinc finger domain binding / fertilization / DNA methylation-dependent constitutive heterochromatin formation / cellular response to cocaine / organ growth / negative regulation of gene expression via chromosomal CpG island methylation / regulation of DNA replication / Transcriptional Regulation by E2F6 / RNA Polymerase I Transcription Initiation / behavioral response to cocaine / Transcriptional Regulation by VENTX / spermatid development / long-term memory / response to fungicide / cellular response to starvation / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / transcription corepressor binding / Transferases; Transferring one-carbon groups; Methyltransferases / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / promoter-specific chromatin binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Regulation of TP53 Activity through Methylation / PKMTs methylate histone lysines / p53 binding / cellular response to xenobiotic stimulus / Senescence-Associated Secretory Phenotype (SASP) / response to ethanol / nuclear speck / chromatin / negative regulation of transcription by RNA polymerase II / enzyme binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Histone-lysine N-methyltransferase EHMT2 / Histone-lysine N-methyltransferase EHMT1/EHMT2 / : / Histone-lysine N-methyltransferase EHMT1/EHMT2, Cys-rich region / Pre-SET motif / Pre-SET domain / Pre-SET domain profile. / N-terminal to some SET domains / Beta-clip-like / SET domain ...Histone-lysine N-methyltransferase EHMT2 / Histone-lysine N-methyltransferase EHMT1/EHMT2 / : / Histone-lysine N-methyltransferase EHMT1/EHMT2, Cys-rich region / Pre-SET motif / Pre-SET domain / Pre-SET domain profile. / N-terminal to some SET domains / 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 / Ankyrin repeat / Beta Complex / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-DXQ / S-ADENOSYL-L-HOMOCYSTEINE / Histone-lysine N-methyltransferase EHMT2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsDong, A. / Wasney, G.A. / Liu, F. / Chen, X. / Allali-Hassani, A. / Senisterra, G. / Chau, I. / Bountra, C. / Weigelt, J. / Edwards, A.M. ...Dong, A. / Wasney, G.A. / Liu, F. / Chen, X. / Allali-Hassani, A. / Senisterra, G. / Chau, I. / Bountra, C. / Weigelt, J. / Edwards, A.M. / Arrowsmith, C.H. / Frye, S.V. / Bochkarev, A. / Brown, P.J. / Jin, J. / Vedadi, M. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2009
Title: Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a.
Authors: Liu, F. / Chen, X. / Allali-Hassani, A. / Quinn, A.M. / Wasney, G.A. / Dong, A. / Barsyte, D. / Kozieradzki, I. / Senisterra, G. / Chau, I. / Siarheyeva, A. / Kireev, D.B. / Jadhav, A. / ...Authors: Liu, F. / Chen, X. / Allali-Hassani, A. / Quinn, A.M. / Wasney, G.A. / Dong, A. / Barsyte, D. / Kozieradzki, I. / Senisterra, G. / Chau, I. / Siarheyeva, A. / Kireev, D.B. / Jadhav, A. / Herold, J.M. / Frye, S.V. / Arrowsmith, C.H. / Brown, P.J. / Simeonov, A. / Vedadi, M. / Jin, J.
History
DepositionOct 7, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software / Item: _software.name
Revision 1.3Sep 6, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms / struct_conn / struct_ref_seq_dif / struct_site
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_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_seq_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details / _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: Histone-lysine N-methyltransferase, H3 lysine-9 specific 3
B: Histone-lysine N-methyltransferase, H3 lysine-9 specific 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,61520
Polymers65,2102
Non-polymers2,40518
Water8,269459
1
A: Histone-lysine N-methyltransferase, H3 lysine-9 specific 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,80810
Polymers32,6051
Non-polymers1,2039
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone-lysine N-methyltransferase, H3 lysine-9 specific 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,80810
Polymers32,6051
Non-polymers1,2039
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2650 Å2
ΔGint-34 kcal/mol
Surface area24310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.674, 78.074, 72.507
Angle α, β, γ (deg.)90.00, 91.81, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Histone-lysine N-methyltransferase, H3 lysine-9 specific 3 / Protein G9a / Histone H3-K9 methyltransferase 3 / H3-K9-HMTase 3 / Euchromatic histone-lysine N- ...Protein G9a / Histone H3-K9 methyltransferase 3 / H3-K9-HMTase 3 / Euchromatic histone-lysine N-methyltransferase 2 / HLA-B-associated transcript 8 / Lysine N-methyltransferase 1C


Mass: 32604.924 Da / Num. of mol.: 2 / Fragment: UNP residues 913-1193, SET domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EHMT2, BAT8, C6orf30, G9A, KMT1C, NG36 / Plasmid: p28a-LIC / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q96KQ7, histone-lysine N-methyltransferase

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Non-polymers , 6 types, 477 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Type: L-peptide linking / Mass: 384.411 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H20N6O5S
#4: Chemical ChemComp-DXQ / 7-[3-(dimethylamino)propoxy]-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine


Mass: 485.665 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H43N7O2
#5: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 2 / Source method: obtained synthetically
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 459 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsLIGAND DXQ IS REFERRED AS 2,4-DIAMINO-7-AMINOALKOXY-QUINAZOLINE IN TITLE

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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: 2.46 Å3/Da / Density % sol: 49.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.2M sodium fluoride, 0.1M Bis-Tris phosphate pH 6.0, 18% polyethylene glycol 3350 and 10% ethylene glycol, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Sep 21, 2009 / Details: VeriMax HR
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. all: 67707 / Num. obs: 67707 / % possible obs: 97.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.8 % / Biso Wilson estimate: 30.2 Å2 / Rmerge(I) obs: 0.044 / Rsym value: 0.044 / Net I/σ(I): 13
Reflection shellResolution: 1.7→1.73 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.727 / Mean I/σ(I) obs: 1.26 / Num. unique all: 2369 / Rsym value: 0.727 / % possible all: 67.6

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Processing

Software
NameVersionClassification
SBC-Collectdata collection
PHASERphasing
REFMAC5.5.0102refinement
Coot0.5.2model building
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2O8J

2o8j


Resolution: 1.7→29.58 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.93 / SU B: 3.091 / SU ML: 0.099 / Cross valid method: THROUGHOUT / σ(I): 0 / ESU R: 0.115 / ESU R Free: 0.123 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2643 1372 2 %RANDOM
Rwork0.2095 ---
all0.21061 0 --
obs0.21061 66303 96.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.946 Å2
Baniso -1Baniso -2Baniso -3
1--2.52 Å20 Å21.75 Å2
2--0.03 Å20 Å2
3---2.6 Å2
Refinement stepCycle: LAST / Resolution: 1.7→29.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4190 0 136 459 4785
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0214429
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3091.9726022
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5695541
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.57923.767215
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.96915660
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.7391534
X-RAY DIFFRACTIONr_chiral_restr0.0820.2646
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213440
X-RAY DIFFRACTIONr_gen_planes_other
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_it0.7551.52713
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.39324345
X-RAY DIFFRACTIONr_scbond_it1.84131716
X-RAY DIFFRACTIONr_scangle_it2.8754.51677
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.697→1.741 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.466 65 -
Rwork0.427 3464 -
obs--68.83 %

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