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

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Basic information

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


Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / mitotic cell cycle 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 ...Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / mitotic cell cycle 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-dependent protein serine/threonine kinase regulator activity / positive regulation of DNA biosynthetic process / 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 / cyclin-dependent protein kinase activity / G2 Phase / Y chromosome / 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 / cochlea development / X chromosome / PTK6 Regulates Cell Cycle / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / regulation of DNA replication / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / 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 / animal organ regeneration / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Activation of ATR in response to replication stress / Cajal body / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of G2/M transition of mitotic cell cycle / cellular response to platelet-derived growth factor stimulus / regulation of mitotic cell cycle / cellular response to nitric oxide / post-translational protein modification / cyclin binding / positive regulation of DNA replication / male germ cell nucleus / meiotic cell cycle / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / cellular response to estradiol stimulus / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / G1/S transition of mitotic cell cycle / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / positive regulation of fibroblast proliferation / G2/M transition of mitotic cell cycle / 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 / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / DNA replication / chromosome, telomeric region / endosome / Ub-specific processing proteases / chromatin remodeling / protein domain specific binding / protein phosphorylation / cell division / protein serine/threonine kinase activity / protein serine kinase activity / DNA repair / DNA-templated transcription / centrosome / positive regulation of cell population proliferation / 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, C-terminal domain / Cyclin_C / Cyclin-like ...Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin-like / 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 / 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-4QE / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 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 18, 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 1.2Oct 23, 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)128,8596
Polymers128,1844
Non-polymers6752
Water18010
1
A: CYCLIN-DEPENDENT KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,4303
Polymers64,0922
Non-polymers3371
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4060 Å2
ΔGint-17.6 kcal/mol
Surface area23370 Å2
MethodPISA
2
C: CYCLIN-DEPENDENT KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,4303
Polymers64,0922
Non-polymers3371
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4130 Å2
ΔGint-15.2 kcal/mol
Surface area22530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.110, 135.443, 149.370
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: 29624.297 Da / Num. of mol.: 2 / Fragment: CDK-ACTIVATING FRAGMENT, RESIDUES 175-432
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-4QE / 6-(cyclohexylmethoxy)-8-(2-methylphenyl)-9H-purin-2-amine


Mass: 337.419 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H23N5O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 2.92 Å3/Da / Density % sol: 57.94 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.934
DetectorType: ADSC QUANTUM 4 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 2.85→22 Å / Num. obs: 33733 / % possible obs: 94 % / Observed criterion σ(I): 0 / Redundancy: 3.21 % / Rmerge(I) obs: 0.12 / Net I/σ(I): 10.1
Reflection shellResolution: 2.85→3 Å / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 1.5 / % possible all: 64.7

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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: 2.85→22.34 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.878 / SU B: 44.014 / SU ML: 0.362 / Cross valid method: THROUGHOUT / ESU R Free: 0.401 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.25806 1671 5 %RANDOM
Rwork0.21711 ---
obs0.21916 32029 93.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 58.092 Å2
Baniso -1Baniso -2Baniso -3
1-1.46 Å20 Å20 Å2
2--2.75 Å20 Å2
3----4.21 Å2
Refinement stepCycle: LAST / Resolution: 2.85→22.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8695 0 50 10 8755
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0199045
X-RAY DIFFRACTIONr_bond_other_d0.0020.028802
X-RAY DIFFRACTIONr_angle_refined_deg1.8341.98412288
X-RAY DIFFRACTIONr_angle_other_deg2.4433.00220295
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.58651089
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.7323.928387
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.847151583
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2281543
X-RAY DIFFRACTIONr_chiral_restr0.1060.21387
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0219959
X-RAY DIFFRACTIONr_gen_planes_other0.0050.022026
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_it0.2280.7394359
X-RAY DIFFRACTIONr_mcbond_other0.2280.7394358
X-RAY DIFFRACTIONr_mcangle_it0.3911.1095447
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.3530.8454686
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: 2.85→2.923 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 58 -
Rwork0.337 1153 -
obs--47.21 %
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)
12.1027-0.5676-1.09471.73030.31621.98340.0443-0.1932-0.05110.24560.0269-0.1918-0.12210.276-0.07120.1009-0.0229-0.06670.041-0.02440.5984-6.756-26.31710.088
22.19550.54150.85522.72220.23713.2385-0.09850.21430.1731-0.17530.09980.0566-0.37040.1088-0.00130.1947-0.00650.04710.02250.02080.5121-21.7730.244-2.669
34.0307-0.13810.56252.31630.12792.7546-0.1976-1.030.4853-0.0619-0.01810.1994-0.5424-1.19040.21580.5710.2575-0.05310.7644-0.28830.6614-44.5913.07932.158
44.0757-0.4670.50093.3743-0.50962.41460.1707-0.6048-0.5683-0.28630.15430.7070.6282-1.3442-0.3250.5699-0.4903-0.08840.84720.10590.7133-44.755-19.65235.021
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A0 - 296
2X-RAY DIFFRACTION2B175 - 432
3X-RAY DIFFRACTION3C0 - 296
4X-RAY DIFFRACTION4D175 - 432

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