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- PDB-2ydi: Discovery of Checkpoint Kinase Inhibitor AZD7762 by Structure Bas... -

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Basic information

Entry
Database: PDB / ID: 2ydi
TitleDiscovery of Checkpoint Kinase Inhibitor AZD7762 by Structure Based Design and Optimization of Thiophene Carboxamide Ureas
ComponentsSERINE/THREONINE-PROTEIN KINASE CHK1
KeywordsTRANSFERASE / CHK
Function / homology
Function and homology information


negative regulation of G0 to G1 transition / apoptotic process involved in development / negative regulation of DNA biosynthetic process / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / regulation of mitotic centrosome separation / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / negative regulation of gene expression, epigenetic / nucleus organization ...negative regulation of G0 to G1 transition / apoptotic process involved in development / negative regulation of DNA biosynthetic process / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / regulation of mitotic centrosome separation / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / negative regulation of gene expression, epigenetic / nucleus organization / cellular response to caffeine / mitotic G2 DNA damage checkpoint signaling / Transcriptional Regulation by E2F6 / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / signal transduction in response to DNA damage / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Activation of ATR in response to replication stress / positive regulation of cell cycle / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / condensed nuclear chromosome / replication fork / TP53 Regulates Transcription of DNA Repair Genes / peptidyl-threonine phosphorylation / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Signaling by SCF-KIT / G2/M DNA damage checkpoint / cellular response to mechanical stimulus / G2/M transition of mitotic cell cycle / regulation of cell population proliferation / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / DNA replication / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H3T6 kinase activity / histone H2AS1 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / protein phosphorylation / chromatin remodeling / protein domain specific binding / intracellular membrane-bounded organelle / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / apoptotic process / DNA damage response / chromatin / protein-containing complex / extracellular space / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Checkpoint kinase 1, catalytic domain / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Checkpoint kinase 1, catalytic domain / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-YDI / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsRead, J.A. / Breed, J. / Haye, H. / McCall, E. / Rowsell, S. / Vallentine, A. / White, A.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery of Checkpoint Kinase Inhibitor (S)-5-(3-Fluorophenyl)-N-(Piperidin-3-Yl)-3-Ureidothiophene-2-Carboxamide (Azd7762) by Structure-Based Design and Optimization of Thiophenecarboxamide Ureas.
Authors: Oza, V. / Ashwell, S. / Almeida, L. / Brassil, P. / Breed, J. / Deng, C. / Gero, T. / Grondine, M. / Horn, C. / Ioannidis, S. / Liu, D. / Lyne, P. / Newcombe, N. / Pass, M. / Read, J.A. / ...Authors: Oza, V. / Ashwell, S. / Almeida, L. / Brassil, P. / Breed, J. / Deng, C. / Gero, T. / Grondine, M. / Horn, C. / Ioannidis, S. / Liu, D. / Lyne, P. / Newcombe, N. / Pass, M. / Read, J.A. / Ready, S. / Rowsell, S. / Su, M. / Toader, D. / Vasbinder, M. / Yu, D. / Yu, Y. / Xue, Y. / Zabludoff, S. / Janetka, J.
History
DepositionMar 21, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 4, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 27, 2012Group: Other
Revision 1.2Apr 3, 2019Group: Data collection / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc / pdbx_database_status
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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 / _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

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Assembly

Deposited unit
A: SERINE/THREONINE-PROTEIN KINASE CHK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4873
Polymers33,0431
Non-polymers4442
Water5,981332
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.069, 65.989, 58.252
Angle α, β, γ (deg.)90.00, 93.79, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein SERINE/THREONINE-PROTEIN KINASE CHK1 / CHK1 CHECKPOINT KINASE


Mass: 33042.988 Da / Num. of mol.: 1 / Fragment: CHK1KD, RESIDUES 1-289
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: O14757, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-YDI / 5-[4-(2-DIMETHYLAMINOETHYLOXY)PHENYL]-2-UREIDO-THIOPHENE-3-CARBOXAMIDE


Mass: 348.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H20N4O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 332 / 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: 2.32 Å3/Da / Density % sol: 47 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX9.6 / Wavelength: 0.86
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Dec 5, 2001 / Details: MIRRORS
RadiationMonochromator: SI111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.86 Å / Relative weight: 1
ReflectionResolution: 1.6→37.16 Å / Num. obs: 39316 / % possible obs: 87.6 % / Observed criterion σ(I): 2 / Redundancy: 2.2 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 6.2
Reflection shellResolution: 1.6→1.69 Å / Redundancy: 1.2 % / Rmerge(I) obs: 0.2 / Mean I/σ(I) obs: 4 / % possible all: 39.7

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→37.16 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.949 / SU B: 3.265 / SU ML: 0.052 / Cross valid method: THROUGHOUT / ESU R: 0.086 / ESU R Free: 0.088 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.20045 1200 3.1 %RANDOM
Rwork0.16671 ---
obs0.16773 38116 87.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 27.11 Å2
Baniso -1Baniso -2Baniso -3
1--0.63 Å20 Å21.08 Å2
2--1.31 Å20 Å2
3----0.54 Å2
Refinement stepCycle: LAST / Resolution: 1.6→37.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2205 0 29 332 2566
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222300
X-RAY DIFFRACTIONr_bond_other_d0.0010.021554
X-RAY DIFFRACTIONr_angle_refined_deg1.2721.9793128
X-RAY DIFFRACTIONr_angle_other_deg0.8633796
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2025282
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.5124.327104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.70215389
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2841514
X-RAY DIFFRACTIONr_chiral_restr0.0730.2339
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212571
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02444
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_it0.7011.51402
X-RAY DIFFRACTIONr_mcbond_other0.1451.5558
X-RAY DIFFRACTIONr_mcangle_it1.29722266
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.9493898
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.214.5860
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: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.292 35 -
Rwork0.245 1164 -
obs--36.58 %
Refinement TLS params.Method: refined / Origin x: 5.3858 Å / Origin y: 0.092 Å / Origin z: 6.6004 Å
111213212223313233
T0.0329 Å2-0.002 Å2-0.0181 Å2-0.0032 Å20 Å2--0.0343 Å2
L0.268 °2-0.0679 °2-0.1609 °2-0.1752 °20.0556 °2--0.5419 °2
S-0.0187 Å °-0.001 Å °-0.0049 Å °0.0286 Å °-0.002 Å °0.0179 Å °0.0452 Å °0.0267 Å °0.0207 Å °

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