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- PDB-4cfu: Structure-based design of C8-substituted O6-cyclohexylmethoxyguan... -
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Basic information
Entry | Database: PDB / ID: 4cfu | ||||||
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Title | Structure-based design of C8-substituted O6-cyclohexylmethoxyguanine CDK1 and 2 inhibitors. | ||||||
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![]() | TRANSFERASE / STRUCTURE-BASED DRUG DESIGN / CONFORMATIONAL RESTRAINT / REVERSED BINDING MODE | ||||||
Function / homology | ![]() Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / mitotic cell cycle phase transition / 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 / response to glucagon ...Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / mitotic cell cycle phase transition / 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 / response to glucagon / cellular response to cocaine / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to insulin-like growth factor stimulus / positive regulation of DNA biosynthetic process / cochlea development / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cellular response to platelet-derived growth factor stimulus / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / cyclin-dependent protein kinase activity / 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 / X chromosome / PTK6 Regulates Cell Cycle / regulation of DNA replication / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / cellular response to nitric oxide / cyclin-dependent protein kinase holoenzyme complex / cyclin-dependent kinase / animal organ regeneration / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / 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 / Cajal body / Cyclin A:Cdk2-associated events at S phase entry / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of mitotic cell cycle / regulation of G2/M transition of mitotic cell cycle / cyclin binding / post-translational protein modification / : / meiotic cell cycle / positive regulation of DNA replication / male germ cell nucleus / cellular response to estradiol stimulus / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / SCF(Skp2)-mediated degradation of p27/p21 / Meiotic recombination / Orc1 removal from chromatin / G1/S transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / G2/M transition of mitotic cell cycle / Cyclin D associated events in G1 / cellular senescence / positive regulation of fibroblast proliferation / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / cellular response to hypoxia / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / DNA replication / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / chromosome, telomeric region / Ub-specific processing proteases / endosome / chromatin remodeling / protein domain specific binding / cell division / protein phosphorylation / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / DNA-templated transcription / centrosome / positive regulation of cell population proliferation / protein kinase binding / positive regulation of DNA-templated transcription Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Carbain, 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. | ||||||
![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 461.3 KB | Display | ![]() |
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PDB format | ![]() | 378.7 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.1 MB | Display | ![]() |
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Full document | ![]() | 1.1 MB | Display | |
Data in XML | ![]() | 48 KB | Display | |
Data in CIF | ![]() | 67.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 1w8cC ![]() 4cfmC ![]() 4cfnC ![]() 4cfvC ![]() 4cfwC ![]() 4cfxC ![]() 1h1sS C: citing same article ( S: Starting model for refinement |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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1 | ![]()
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2 | ![]()
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Unit cell |
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Components
-Protein , 3 types, 4 molecules ACBD
#1: Protein | Mass: 34451.883 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Details: PHOSPHORYLATED ON RESIDUE T160 / Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P24941, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase #2: Protein | | Mass: 30002.631 Da / Num. of mol.: 1 / Fragment: CDK-ACTIVATING FRAGMENT, RESIDUES 172-432 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #3: Protein | | Mass: 30089.666 Da / Num. of mol.: 1 / Fragment: CDK-ACTIVATING FRAGMENT, RESIDUES 172-432 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Non-polymers , 3 types, 493 molecules ![](data/chem/img/2WC.gif)
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#4: Chemical | #5: Chemical | #6: Water | ChemComp-HOH / | |
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-Details
Sequence details | N-TERMINAL 3C PROTEASE SITE. SEQUENCE OF CHAINS B AND D UNCONFIRME |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 2.82 Å3/Da / Density % sol: 56.4 % / Description: NONE |
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Crystal grow | Details: 50 MM AMMONIUM ACETATE, 10% PEG-3350, 15 MM NACL, 100 MM HEPES, PH = 7.4, 10% DMSO |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: RAYONIX SX-165mm / Detector: CCD |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 2.2→19.8 Å / Num. obs: 74525 / % possible obs: 99.6 % / Observed criterion σ(I): 0 / Redundancy: 3.24 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 11.9 |
Reflection shell | Resolution: 2.2→2.32 Å / Rmerge(I) obs: 0.36 / Mean I/σ(I) obs: 3.6 / % possible all: 100 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: PDB ENTRY 1H1S Resolution: 2.2→19.82 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.934 / SU B: 10.845 / SU ML: 0.138 / Cross valid method: THROUGHOUT / ESU R: 0.219 / ESU R Free: 0.181 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 35.756 Å2
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Refinement step | Cycle: LAST / Resolution: 2.2→19.82 Å
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Refine LS restraints |
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