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- PDB-5fp6: Structure of cyclin-dependent kinase 2 with small-molecule ligand... -

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Basic information

Entry
Database: PDB / ID: 5fp6
TitleStructure of cyclin-dependent kinase 2 with small-molecule ligand 3-(4,7-dichloro-1H-indol-3-yl)prop-2-yn-1-ol (AT17833) in an alternate binding site.
ComponentsCYCLIN-DEPENDENT KINASE 2
KeywordsTRANSFERASE / KINASE / MITOSIS / CELL CYCLE / FRAGMENT SCREENING / ALTERNATE BINDING SITE.
Function / homology
Function and homology information


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 ...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) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / centrosome duplication / G0 and Early G1 / Telomere Extension By Telomerase / 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 / Cajal body / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / 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 / 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 / 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 / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / 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 / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / chromosome, telomeric region / DNA replication / protein phosphorylation / endosome / 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 / positive regulation of DNA-templated transcription / magnesium ion binding / negative regulation of transcription by RNA polymerase II / signal transduction / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
: / 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 ...: / 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
3-(4,7-dichloro-1H-indol-3-yl)prop-2-yn-1-ol / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsJhoti, H. / Ludlow, R.F. / O'Reilly, M. / Saini, H.K. / Tickle, I.J. / Verdonk, M.
Citation
Journal: Proc.Natl.Acad.Sci.USA / Year: 2015
Title: Detection of Secondary Binding Sites in Proteins Using Fragment Screening.
Authors: Ludlow, R.F. / Verdonk, M.L. / Saini, H.K. / Tickle, I.J. / Jhoti, H.
#1: Journal: J.Med.Chem. / Year: 2008
Title: Identification of N-(4-Piperidinyl)-4-(2,6-Dichlorobenzoylamino)-1H-Pyrazole-3-Carboxamide (at7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and ...Title: Identification of N-(4-Piperidinyl)-4-(2,6-Dichlorobenzoylamino)-1H-Pyrazole-3-Carboxamide (at7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design.
Authors: Wyatt, P.G. / Woodhead, A.J. / Berdini, V. / Boulstridge, J.A. / Carr, M.G. / Cross, D.M. / Davis, D.J. / Devine, L.A. / Early, T.R. / Feltell, R.E. / Lewis, E.J. / Mcmenamin, R.L. / ...Authors: Wyatt, P.G. / Woodhead, A.J. / Berdini, V. / Boulstridge, J.A. / Carr, M.G. / Cross, D.M. / Davis, D.J. / Devine, L.A. / Early, T.R. / Feltell, R.E. / Lewis, E.J. / Mcmenamin, R.L. / Navarro, E.F. / O'Brien, M.A. / O'Reilly, M. / Reule, M. / Saxty, G. / Seavers, L.C.A. / Smith, D. / Squires, M.S. / Trewartha, G. / Walker, M.T. / Woolford, A.J.
History
DepositionNov 27, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 23, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2016Group: Database references
Revision 1.2Apr 28, 2021Group: Data collection / Derived calculations / Other / Category: pdbx_database_status / reflns / struct_site
Item: _pdbx_database_status.status_code_sf / _reflns.pdbx_redundancy ..._pdbx_database_status.status_code_sf / _reflns.pdbx_redundancy / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CYCLIN-DEPENDENT KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4573
Polymers33,9761
Non-polymers4802
Water6,071337
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.917, 72.214, 72.198
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: 33976.488 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC1 / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#2: Chemical ChemComp-MFZ / 3-(4,7-dichloro-1H-indol-3-yl)prop-2-yn-1-ol


Mass: 240.085 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H7Cl2NO
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 337 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details3-(4,7-DICHLORO-1H-INDOL-3-YL)PROP-2-YN-1-OL (MFZ): ASTEX COMPOUND REGISTRY AT17833

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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: 2.25 Å3/Da / Density % sol: 45 % / Description: NONE
Crystal growpH: 7.4 / Details: PROTEIN CONCENTRATION: 13.6 MG/ML, pH 7.4

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD / Date: Dec 12, 2007 / Details: MIRROR
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.85→32.3 Å / Num. obs: 24694 / % possible obs: 94.3 % / Observed criterion σ(I): -3.7 / Biso Wilson estimate: 27.83 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 13.2
Reflection shellResolution: 1.85→1.92 Å / Rmerge(I) obs: 0.22 / Mean I/σ(I) obs: 2 / % possible all: 63.3

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
d*TREK9.7data reduction
DTSCALEdata scaling
CSEARCHphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 5FP5

5fp5


Resolution: 1.85→32.29 Å / Cor.coef. Fo:Fc: 0.9397 / Cor.coef. Fo:Fc free: 0.9269 / SU R Cruickshank DPI: 0.172 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.195 / SU Rfree Blow DPI: 0.159 / SU Rfree Cruickshank DPI: 0.15
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2403 1142 4.91 %RANDOM
Rwork0.207 ---
obs0.2086 23282 94.28 %-
Displacement parametersBiso mean: 30.85 Å2
Baniso -1Baniso -2Baniso -3
1-1.9128 Å20 Å20 Å2
2---4.6795 Å20 Å2
3---2.7667 Å2
Refine analyzeLuzzati coordinate error obs: 0.264 Å
Refinement stepCycle: LAST / Resolution: 1.85→32.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2176 0 30 337 2543
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0122279HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.653109HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d747SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes44HARMONIC2
X-RAY DIFFRACTIONt_gen_planes342HARMONIC16
X-RAY DIFFRACTIONt_it2279HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion5.72
X-RAY DIFFRACTIONt_other_torsion18.51
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion294SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2965SEMIHARMONIC4
LS refinement shellResolution: 1.85→1.93 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.3147 86 4.44 %
Rwork0.254 1850 -
all0.2568 1936 -
obs--65.51 %
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)
10.59580.1152-0.2220.02910.35930.3914-0.0037-0.02290.009-0.0103-0.00990.0406-0.0024-0.02540.0136-0.07650.0129-0.0040.06270.0479-0.000717.60282.18864.7304
20.32180.2024-0.71710-0.1970.65460.0033-0.02010.00470.0133-0.00490.0074-0.00840.00680.00160.00710.02940.00370.01980.0546-0.027131.9232.587557.7899
31.0165-0.15030.32510.4794-0.08091.26550.00780.0180.02020.0039-0.01370.0096-0.05220.05310.0058-0.04840.00630.0047-0.02130.0061-0.037133.48316.668441.8204
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|1 - A|83 }
2X-RAY DIFFRACTION2{ A|130 - A|164 }
3X-RAY DIFFRACTION3{ A|84 - A|129 A|165 - A|294 }

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