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- PDB-5fp5: Structure of cyclin-dependent kinase 2 with small-molecule ligand... -

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Basic information

Entry
Database: PDB / ID: 5fp5
TitleStructure of cyclin-dependent kinase 2 with small-molecule ligand 4- fluorobenzoic acid (AT222) 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 / 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 ...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 / 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 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 / 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 / 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 / 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 / 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 / DNA replication / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / chromosome, telomeric region / 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 / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / magnesium ion binding / signal transduction / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
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. ...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
4-fluorobenzoic acid / ACETYL GROUP / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.16 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 9, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 23, 2015Group: Database references
Revision 1.2Jan 13, 2016Group: Database references
Revision 2.0Aug 28, 2019Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / citation ...atom_site / citation / citation_author / reflns / struct_conn
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site.type_symbol / _citation.page_last / _citation_author.name / _reflns.pdbx_Rmerge_I_obs / _struct_conn.pdbx_leaving_atom_flag
Revision 2.1Apr 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 2.2Jan 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)34,3014
Polymers33,9761
Non-polymers3243
Water5,783321
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.677, 71.698, 72.382
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-1Y6 / 4-fluorobenzoic acid


Mass: 140.112 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H5FO2
#3: Chemical ChemComp-ACE / ACETYL GROUP


Mass: 44.053 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H4O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 321 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details4-FLUOROBENZOIC ACID (L02): ASTEX COMPOUND REGISTRY AT222 4-FLUOROBENZOIC ACID (L01): ASTEX ...4-FLUOROBENZOIC ACID (L02): ASTEX COMPOUND REGISTRY AT222 4-FLUOROBENZOIC ACID (L01): ASTEX COMPOUND REGISTRY AT222

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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: 2.35 Å3/Da / Density % sol: 47 % / Description: NONE
Crystal growpH: 7.4
Details: 10MM HEPES/NAOH PH7.4 15MM NACL PROTEIN CONCENTRATION: 8.6 MG/ML

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Type: SRS / Wavelength: 1
DetectorType: ADSC CCD / Detector: CCD / Date: May 2, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.16→30 Å / Num. obs: 14466 / % possible obs: 93.1 % / Observed criterion σ(I): -3.7 / Biso Wilson estimate: 32.2 Å2

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
d*TREKdata reduction
DTSCALEdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1HCK

1hck


Resolution: 2.16→30.01 Å / Cor.coef. Fo:Fc: 0.9405 / Cor.coef. Fo:Fc free: 0.9067 / SU R Cruickshank DPI: 0.294 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.392 / SU Rfree Blow DPI: 0.244 / SU Rfree Cruickshank DPI: 0.229
RfactorNum. reflection% reflectionSelection details
Rfree0.253 731 5.05 %RANDOM
Rwork0.1866 ---
obs0.1898 14466 93.12 %-
Displacement parametersBiso mean: 32.09 Å2
Baniso -1Baniso -2Baniso -3
1--1.8404 Å20 Å20 Å2
2--2.6526 Å20 Å2
3----0.8121 Å2
Refine analyzeLuzzati coordinate error obs: 0.242 Å
Refinement stepCycle: LAST / Resolution: 2.16→30.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2076 0 23 321 2420
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0112160HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.042934HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d708SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes40HARMONIC2
X-RAY DIFFRACTIONt_gen_planes328HARMONIC16
X-RAY DIFFRACTIONt_it2160HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion5.87
X-RAY DIFFRACTIONt_other_torsion18.01
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion273SEMIHARMONIC5
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_contact2776SEMIHARMONIC4
LS refinement shellResolution: 2.16→2.33 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2883 138 4.93 %
Rwork0.1966 2660 -
all0.2011 2798 -
obs--88.89 %
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)
11.1178-1.1947-0.48480.07480.60360.4592-0.00730.0007-0.0082-0.05060.03380.06990.0131-0.0561-0.0265-0.0667-0.01110.01350.04070.09270.00620.11371.42666.3227
20.37620.2176-1.235800.16740.77240.0006-0.0309-0.00310.0079-0.01380.0123-0.00040.00590.0132-0.01230.0092-0.00250.03920.0764-0.040331.63352.191358.0783
31.1992-0.42180.33860.7243-0.34211.33730.0050.00260.00810.0255-0.00950.0056-0.0080.04760.0046-0.03640.00780.002-0.0192-0.0013-0.064533.46416.535642.281
Refinement TLS groupSelection details: CHAIN A

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