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- PDB-6b3e: Crystal structure of human CDK12/CyclinK in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 6b3e
TitleCrystal structure of human CDK12/CyclinK in complex with an inhibitor
Components
  • Cyclin-K
  • Cyclin-dependent kinase 12
KeywordsTRANSFERASE/INHIBITOR / Inhibitor / complex / kinase / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


cyclin K-CDK12 complex / cyclin K-CDK13 complex / nuclear cyclin-dependent protein kinase holoenzyme complex / regulation of MAP kinase activity / cyclin/CDK positive transcription elongation factor complex / negative regulation by host of viral genome replication / negative regulation of stem cell differentiation / cyclin-dependent protein serine/threonine kinase activator activity / positive regulation of DNA-templated transcription, elongation / [RNA-polymerase]-subunit kinase ...cyclin K-CDK12 complex / cyclin K-CDK13 complex / nuclear cyclin-dependent protein kinase holoenzyme complex / regulation of MAP kinase activity / cyclin/CDK positive transcription elongation factor complex / negative regulation by host of viral genome replication / negative regulation of stem cell differentiation / cyclin-dependent protein serine/threonine kinase activator activity / positive regulation of DNA-templated transcription, elongation / [RNA-polymerase]-subunit kinase / regulation of cyclin-dependent protein serine/threonine kinase activity / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / RNA polymerase II transcribes snRNA genes / regulation of signal transduction / cyclin-dependent kinase / Formation of HIV elongation complex in the absence of HIV Tat / cyclin-dependent protein serine/threonine kinase activity / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / RNA Polymerase II Pre-transcription Events / RNA polymerase II CTD heptapeptide repeat kinase activity / cyclin binding / RNA splicing / TP53 Regulates Transcription of DNA Repair Genes / positive regulation of transcription elongation by RNA polymerase II / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / mRNA processing / transcription by RNA polymerase II / protein autophosphorylation / protein kinase activity / nuclear speck / cell cycle / cell division / protein serine kinase activity / DNA damage response / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus
Similarity search - Function
Cyclin-T2-like, C-terminal domain / Haspin like kinase domain / Cyclin, C-terminal domain / Cyclin_C / Cyclin/Cyclin-like subunit Ssn8 / Cyclin-like / Cyclin A; domain 1 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like ...Cyclin-T2-like, C-terminal domain / Haspin like kinase domain / Cyclin, C-terminal domain / Cyclin_C / Cyclin/Cyclin-like subunit Ssn8 / 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 / 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
Chem-CJM / Cyclin-K / Cyclin-dependent kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.06 Å
AuthorsFerguson, A.D.
CitationJournal: ChemMedChem / Year: 2018
Title: Structure-Based Design of Selective Noncovalent CDK12 Inhibitors.
Authors: Johannes, J.W. / Denz, C.R. / Su, N. / Wu, A. / Impastato, A.C. / Mlynarski, S. / Varnes, J.G. / Prince, D.B. / Cidado, J. / Gao, N. / Haddrick, M. / Jones, N.H. / Li, S. / Li, X. / Liu, Y. ...Authors: Johannes, J.W. / Denz, C.R. / Su, N. / Wu, A. / Impastato, A.C. / Mlynarski, S. / Varnes, J.G. / Prince, D.B. / Cidado, J. / Gao, N. / Haddrick, M. / Jones, N.H. / Li, S. / Li, X. / Liu, Y. / Nguyen, T.B. / O'Connell, N. / Rivers, E. / Robbins, D.W. / Tomlinson, R. / Yao, T. / Zhu, X. / Ferguson, A.D. / Lamb, M.L. / Manchester, J.I. / Guichard, S.
History
DepositionSep 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 27, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 3, 2018Group: Database references / Category: citation
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 14, 2018Group: Database references / Category: citation / citation_author / Item: _citation.title
Revision 1.3Feb 21, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.4Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-dependent kinase 12
B: Cyclin-K
C: Cyclin-dependent kinase 12
D: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)138,14811
Polymers137,0004
Non-polymers1,1487
Water1629
1
A: Cyclin-dependent kinase 12
B: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,1056
Polymers68,5002
Non-polymers6054
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2430 Å2
ΔGint-9 kcal/mol
Surface area25170 Å2
MethodPISA
2
C: Cyclin-dependent kinase 12
D: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,0435
Polymers68,5002
Non-polymers5433
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2200 Å2
ΔGint-8 kcal/mol
Surface area25510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.140, 77.260, 90.640
Angle α, β, γ (deg.)76.530, 85.280, 78.220
Int Tables number1
Space group name H-MP1

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Components

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Protein , 2 types, 4 molecules ACBD

#1: Protein Cyclin-dependent kinase 12 / Cdc2-related kinase / arginine/serine-rich / CrkRS / Cell division cycle 2-related protein kinase 7 ...Cdc2-related kinase / arginine/serine-rich / CrkRS / Cell division cycle 2-related protein kinase 7 / CDC2-related protein kinase 7 / Cell division protein kinase 12 / hCDK12


Mass: 37127.969 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK12, CRK7, CRKRS, KIAA0904 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9NYV4, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein Cyclin-K


Mass: 31372.125 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNK, CPR4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O75909

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Non-polymers , 4 types, 16 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-CJM / 2-[(2S)-1-(6-{[(4,5-difluoro-1H-benzimidazol-2-yl)methyl]amino}-9-ethyl-9H-purin-2-yl)piperidin-2-yl]ethan-1-ol


Mass: 456.492 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H26F2N8O
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 9 / Source method: isolated from a natural source / Formula: H2O

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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: 2.44 Å3/Da / Density % sol: 49.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1 M Bis-Tris, pH 6.5, 20.5% PEG 3350, 0.4 M MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 5, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.06→88.08 Å / Num. obs: 22962 / % possible obs: 93.5 % / Redundancy: 3.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.055 / Rrim(I) all: 0.028 / Net I/av σ(I): 16.6 / Net I/σ(I): 16.6
Reflection shellResolution: 3.05→3.06 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.528 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 260 / CC1/2: 0.897 / Rpim(I) all: 0.445 / Rrim(I) all: 0.63 / % possible all: 95.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimlessdata scaling
MOLREPphasing
BUSTERrefinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NST

4nst


Resolution: 3.06→88.08 Å / Rfactor Rfree error: 0.01 / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflectionSelection details
Rfree0.212 1106 4.85 %RANDOM
Rwork0.19 ---
obs0.191 22813 93.4 %-
Displacement parametersBiso max: 235.89 Å2 / Biso mean: 88.7713 Å2 / Biso min: 30.01 Å2
Refinement stepCycle: LAST / Resolution: 3.06→88.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9030 0 80 9 9119

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