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- PDB-7m2f: CDK2 with compound 14 inhibitor with carboxylate -

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Basic information

Entry
Database: PDB / ID: 7m2f
TitleCDK2 with compound 14 inhibitor with carboxylate
ComponentsCyclin-dependent kinase 2
KeywordsSIGNALING PROTEIN / Transferase/Inhibitor / CDK2 / CDK9 / kinase inhibitor / Transferase-Inhibitor complex
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 / 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 / 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
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
Similarity search - Domain/homology
Chem-YOS / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.632 Å
AuthorsLongenecker, K.L. / Qiu, W. / Korepanova, A. / Tong, Y.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Balancing Properties with Carboxylates: A Lead Optimization Campaign for Selective and Orally Active CDK9 Inhibitors.
Authors: Tong, Y. / Florjancic, A.S. / Clark, R.F. / Lai, C. / Mastracchio, A. / Zhu, G.D. / Smith, M.L. / Kovar, P.J. / Shaw, B. / Albert, D.H. / Qiu, W. / Longenecker, K.L. / Liu, X. / Olson, A.M. ...Authors: Tong, Y. / Florjancic, A.S. / Clark, R.F. / Lai, C. / Mastracchio, A. / Zhu, G.D. / Smith, M.L. / Kovar, P.J. / Shaw, B. / Albert, D.H. / Qiu, W. / Longenecker, K.L. / Liu, X. / Olson, A.M. / Osterling, D.J. / Tahir, S.K. / Phillips, D.C. / Leverson, J.D. / Souers, A.J. / Penning, T.D.
History
DepositionMar 16, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 7, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 28, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Oct 18, 2023Group: 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)34,4402
Polymers33,9761
Non-polymers4641
Water2,342130
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.260, 71.100, 71.660
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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) / Gene: CDK2, CDKN2 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#2: Chemical ChemComp-YOS / [(1r,4r)-4-{4-[4-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydropyridin-1(2H)-yl}cyclohexyl]acetic acid


Mass: 463.544 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H30FN3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 130 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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 Å3/Da / Density % sol: 38.4 %
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 7.5 / Details: 20% PEG 10K, 0.1M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 30, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.632→42.75 Å / Num. obs: 31728 / % possible obs: 91.9 % / Redundancy: 6.2 % / Rmerge(I) obs: 0.053 / Rpim(I) all: 0.023 / Net I/σ(I): 15.8
Reflection shellResolution: 1.632→1.66 Å / Rmerge(I) obs: 0.824 / Num. unique obs: 1690 / Rpim(I) all: 0.351

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (29-NOV-2019)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1B38

1b38


Resolution: 1.632→42.75 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.897 / SU R Cruickshank DPI: 0.118 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.12 / SU Rfree Blow DPI: 0.12 / SU Rfree Cruickshank DPI: 0.12
RfactorNum. reflection% reflectionSelection details
Rfree0.2575 1598 5.04 %RANDOM
Rwork0.2109 ---
obs0.2131 31728 91.9 %-
Displacement parametersBiso max: 75.42 Å2 / Biso mean: 32.54 Å2 / Biso min: 16.97 Å2
Baniso -1Baniso -2Baniso -3
1--0.9776 Å20 Å20 Å2
2---5.2377 Å20 Å2
3---6.2153 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: final / Resolution: 1.632→42.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2270 0 34 130 2434
Biso mean--36.02 38.52 -
Num. residues----281
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d833SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes411HARMONIC5
X-RAY DIFFRACTIONt_it2387HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion300SEMIHARMONIC5
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_contact2088SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2387HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3241HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion3.36
X-RAY DIFFRACTIONt_other_torsion18.19
LS refinement shellResolution: 1.632→1.64 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.1471 24 3.78 %
Rwork-611 -
obs--100 %

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