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

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Basic information

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


negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / negative regulation of DNA biosynthetic process / mitotic G2/M transition checkpoint / negative regulation of mitotic nuclear division / regulation of mitotic centrosome separation / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / nucleus organization ...negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / negative regulation of DNA biosynthetic process / mitotic G2/M transition checkpoint / negative regulation of mitotic nuclear division / regulation of mitotic centrosome separation / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / nucleus organization / negative regulation of gene expression, epigenetic / cellular response to caffeine / Transcriptional Regulation by E2F6 / mitotic G2 DNA damage checkpoint signaling / 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 / regulation of signal transduction by p53 class mediator / DNA damage checkpoint signaling / condensed nuclear chromosome / replication fork / TP53 Regulates Transcription of DNA Repair Genes / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / peptidyl-threonine phosphorylation / 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 / DNA replication / non-specific serine/threonine protein kinase / protein kinase activity / chromatin remodeling / protein phosphorylation / protein domain specific binding / intracellular membrane-bounded organelle / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / DNA damage response / chromatin / apoptotic process / protein-containing complex / extracellular space / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Checkpoint kinase 1, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Checkpoint kinase 1, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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
PHOSPHATE ION / Chem-YDJ / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.85 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 22, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 25, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 27, 2012Group: Other
Revision 1.2Mar 27, 2013Group: Non-polymer description
Revision 1.3Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Apr 3, 2019Group: Data collection / Derived calculations / Source and taxonomy
Category: entity_src_gen / pdbx_seq_map_depositor_info / struct_conn
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_seq_map_depositor_info.one_letter_code_mod / _struct_conn.pdbx_leaving_atom_flag
Revision 1.5Nov 13, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / 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 / _struct_conn.pdbx_leaving_atom_flag / _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: SERINE/THREONINE-PROTEIN KINASE CHK1
B: SERINE/THREONINE-PROTEIN KINASE CHK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7256
Polymers63,8102
Non-polymers9154
Water7,458414
1
A: SERINE/THREONINE-PROTEIN KINASE CHK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3623
Polymers31,9051
Non-polymers4572
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: SERINE/THREONINE-PROTEIN KINASE CHK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3623
Polymers31,9051
Non-polymers4572
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.004, 64.854, 119.999
Angle α, β, γ (deg.)90.00, 98.77, 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: 31904.863 Da / Num. of mol.: 2 / Fragment: CHK1KD, RESIDUES 1-276
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-YDJ / 5-(3-fluorophenyl)-N-[(3S)-3-piperidyl]-3-ureido-thiophene-2-carboxamide


Mass: 362.422 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H19FN4O2S
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 414 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD / Date: Jan 25, 2007 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.85→43.76 Å / Num. obs: 46087 / % possible obs: 84.4 % / Observed criterion σ(I): 2 / Redundancy: 2.44 % / Biso Wilson estimate: 22.5 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 5.8
Reflection shellResolution: 1.85→1.92 Å / Redundancy: 2.35 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 2.2 / % possible all: 78.7

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Processing

Software
NameVersionClassification
REFMAC5.5.0110refinement
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→43.76 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.896 / SU B: 8.253 / SU ML: 0.118 / Cross valid method: THROUGHOUT / ESU R: 0.194 / ESU R Free: 0.177 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.27423 2369 5.1 %RANDOM
Rwork0.22855 ---
obs0.23094 43718 84.41 %-
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: 35.154 Å2
Baniso -1Baniso -2Baniso -3
1--0.88 Å20 Å20.25 Å2
2--0.42 Å20 Å2
3---0.53 Å2
Refinement stepCycle: LAST / Resolution: 1.85→43.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4114 0 60 414 4588
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0224290
X-RAY DIFFRACTIONr_bond_other_d0.0010.022928
X-RAY DIFFRACTIONr_angle_refined_deg1.2431.9825811
X-RAY DIFFRACTIONr_angle_other_deg0.83137132
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7795503
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.09924.3207
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.60715751
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1181528
X-RAY DIFFRACTIONr_chiral_restr0.0730.2619
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214727
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02835
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_it0.6011.52529
X-RAY DIFFRACTIONr_mcbond_other0.121.51014
X-RAY DIFFRACTIONr_mcangle_it1.10624094
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.60631761
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.5194.51717
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: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.34 141 -
Rwork0.277 2939 -
obs--76.22 %
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)
10.62210.0571-0.16130.50590.00240.66070.0237-0.02980.00180.0696-0.0215-0.00870.0458-0.0411-0.00220.0196-0.0027-0.00430.0101-0.00230.0018-7.9451-0.003451.5252
20.72420.0290.0640.52530.01970.82430.04010.07240.0464-0.0706-0.0118-0.0259-0.0601-0.0185-0.02830.02080.00320.010.01390.00490.0060.770914.91127.7125
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A8 - 269
2X-RAY DIFFRACTION2B9 - 269

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