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- PDB-4cfx: Structure-based design of C8-substituted O6-cyclohexylmethoxyguan... -

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Basic information

Entry
Database: PDB / ID: 4cfx
TitleStructure-based design of C8-substituted O6-cyclohexylmethoxyguanine CDK1 and 2 inhibitors.
Components
  • CYCLIN-A2
  • CYCLIN-DEPENDENT KINASE 2
KeywordsCELL CYCLE / STRUCTURE-BASED DRUG DESIGN / CONFORMATIONAL RESTRAINT / REVERSED BINDING MODE
Function / homology
Function and homology information


: / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cellular response to leptin stimulus / male pronucleus / female pronucleus / cellular response to cocaine / response to glucagon ...: / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cellular response to leptin stimulus / male pronucleus / female pronucleus / cellular response to cocaine / response to glucagon / positive regulation of DNA biosynthetic process / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to insulin-like growth factor stimulus / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / Y chromosome / cyclin-dependent protein kinase activity / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / X chromosome / PTK6 Regulates Cell Cycle / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / microtubule organizing center / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / regulation of DNA replication / telomere maintenance in response to DNA damage / centrosome duplication / G0 and Early G1 / cochlea development / Telomere Extension By Telomerase / animal organ regeneration / Activation of the pre-replicative complex / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cajal body / Activation of ATR in response to replication stress / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / cellular response to platelet-derived growth factor stimulus / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / post-translational protein modification / cyclin binding / regulation of mitotic cell cycle / positive regulation of DNA replication / meiotic cell cycle / male germ cell nucleus / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / cellular response to estradiol stimulus / G1/S transition of mitotic cell cycle / peptidyl-serine phosphorylation / DNA Damage/Telomere Stress Induced Senescence / potassium ion transport / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / G2/M transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / positive regulation of fibroblast proliferation / Cyclin D associated events in G1 / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / transcription regulator complex / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / chromosome, telomeric region / DNA replication / protein phosphorylation / endosome / Ub-specific processing proteases / chromatin remodeling / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / positive regulation of cell population proliferation / DNA-templated transcription / centrosome / protein kinase binding
Similarity search - Function
Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin-like / Cyclin, C-terminal domain / Cyclin_C ...Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin-like / Cyclin, C-terminal domain / Cyclin_C / Cyclin A; domain 1 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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
Chem-G6T / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsCarbain, B. / Paterson, D.J. / Anscombe, E. / Campbell, A. / Cano, C. / Echalier, A. / Endicott, J. / Golding, B.T. / Haggerty, K. / Hardcastle, I.R. ...Carbain, B. / Paterson, D.J. / Anscombe, E. / Campbell, A. / Cano, C. / Echalier, A. / Endicott, J. / Golding, B.T. / Haggerty, K. / Hardcastle, I.R. / Jewsbury, P. / Newell, D.R. / Noble, M.E.M. / Roche, C. / Wang, L.Z. / Griffin, R.
CitationJournal: J.Med.Chem. / Year: 2014
Title: 8-Substituted O6-Cyclohexylmethylguanine Cdk2 Inhibitors; Using Structure-Based Inhibitor Design to Optimise an Alternative Binding Mode.
Authors: Carbain, B. / Paterson, D.J. / Anscombe, E. / Campbell-Dexter, A. / Cano, C. / Echalier, A. / Endicott, J. / Golding, B.T. / Haggerty, K. / Hardcastle, I.R. / Jewsbury, P.J. / Newell, D.R. / ...Authors: Carbain, B. / Paterson, D.J. / Anscombe, E. / Campbell-Dexter, A. / Cano, C. / Echalier, A. / Endicott, J. / Golding, B.T. / Haggerty, K. / Hardcastle, I.R. / Jewsbury, P.J. / Newell, D.R. / Noble, M. / Roche, C. / Wang, L. / Griffin, R.J.
History
DepositionNov 19, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 10, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 20, 2023Group: 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 / 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
Revision 1.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CYCLIN-DEPENDENT KINASE 2
B: CYCLIN-A2
C: CYCLIN-DEPENDENT KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,4766
Polymers128,6714
Non-polymers8052
Water1,58588
1
C: CYCLIN-DEPENDENT KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7383
Polymers64,3352
Non-polymers4021
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4300 Å2
ΔGint-15.1 kcal/mol
Surface area24400 Å2
MethodPISA
2
A: CYCLIN-DEPENDENT KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7383
Polymers64,3352
Non-polymers4021
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3860 Å2
ΔGint-13.5 kcal/mol
Surface area24210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.660, 136.560, 149.030
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 CYCLIN-DEPENDENT KINASE 2 / CELL DIVISION PROTEIN KINASE 2 / P33 PROTEIN KINASE


Mass: 34467.926 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: PHOSPHORYLATED ON RESIDUE T160 / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI B (bacteria) / Strain (production host): B834
References: UniProt: P24941, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein CYCLIN-A2 / CYCLIN-A


Mass: 29867.512 Da / Num. of mol.: 2 / Fragment: CDK-ACTIVATING FRAGMENT, RESIDUES 173-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI B (bacteria) / Strain (production host): B834 / References: UniProt: P20248
#3: Chemical ChemComp-G6T / 3-[2-amino-6-(cyclohexylmethoxy)-7H-purin-8-yl]benzenesulfonamide


Mass: 402.471 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H22N6O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 88 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsN-TERMINAL 3C PROTEASE SITE

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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: 2.95 Å3/Da / Density % sol: 58.34 % / Description: NONE
Crystal growDetails: 50 MM AMMONIUM ACETATE, 10% PEG-3350, 15 MM NACL, 100 MM HEPES, PH = 7.4, 10% DMSO

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Type: DIAMOND / Wavelength: 0.8726
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2.95→50.35 Å / Num. obs: 11358 / % possible obs: 98.6 % / Observed criterion σ(I): 0 / Redundancy: 2.68 % / Rmerge(I) obs: 0.11

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1H1S

1h1s


Resolution: 3.5→50.34 Å / Cor.coef. Fo:Fc: 0.899 / Cor.coef. Fo:Fc free: 0.831 / SU B: 79.454 / SU ML: 0.567 / Cross valid method: THROUGHOUT / ESU R Free: 0.687 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.26929 976 5 %RANDOM
Rwork0.20418 ---
obs0.2075 18483 97.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 51.289 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å20 Å20 Å2
2--0.68 Å20 Å2
3----0.68 Å2
Refinement stepCycle: LAST / Resolution: 3.5→50.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9014 0 56 88 9158
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0199524
X-RAY DIFFRACTIONr_bond_other_d0.0020.029220
X-RAY DIFFRACTIONr_angle_refined_deg1.5531.98412980
X-RAY DIFFRACTIONr_angle_other_deg2.4313.00221294
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.85351169
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.33424.01404
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.382151671
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7221546
X-RAY DIFFRACTIONr_chiral_restr0.0930.21461
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02110619
X-RAY DIFFRACTIONr_gen_planes_other0.0030.022137
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_it0.191.2424610
X-RAY DIFFRACTIONr_mcbond_other0.1891.2424609
X-RAY DIFFRACTIONr_mcangle_it0.3331.8625801
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.4651.3924914
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: 3.5→3.591 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.239 73 -
Rwork0.222 1351 -
obs--98.75 %
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)
12.0053-0.6303-1.16911.22980.58182.53630.0114-0.26050.06440.2380.0778-0.1948-0.14490.2372-0.08920.086-0.0126-0.0390.52830.0210.0335-6.417-26.72310.361
21.70660.3802-0.14492.6090.32013.4343-0.08660.06610.0208-0.07260.07220.0861-0.29880.06390.01430.10740.00880.00720.48350.00320.0043-21.6760.131-2.662
33.8662-0.167-1.71651.80930.20061.71630.0706-0.10720.2394-0.0336-0.12240.2901-0.2188-0.14160.05180.40570.0422-0.02560.678-0.14980.2047-47.53512.56533.615
43.42190.11560.58842.5530.07711.84470.1089-0.1734-0.34820.0624-0.16440.57290.28-0.56370.05560.4298-0.18550.06990.7736-0.10630.2041-44.677-20.87534.939
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A0 - 298
2X-RAY DIFFRACTION2B173 - 432
3X-RAY DIFFRACTION3C0 - 298
4X-RAY DIFFRACTION4D173 - 432

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