[English] 日本語
Yorodumi
- PDB-6ckx: Structure of CDK12/CycK in complex with a small molecule inhibito... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 6ckx
TitleStructure of CDK12/CycK in complex with a small molecule inhibitor N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)acetamide
Components
  • Cyclin-K
  • Cyclin-dependent kinase 12
KeywordsTRANSFERASE/INHIBITOR / Kinase / Transferase / Inhibitor / Transferase-Cell Cycle-Inhibitor complex / 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 / RNA polymerase II CTD heptapeptide repeat Y1 kinase activity / RNA polymerase II CTD heptapeptide repeat S2 kinase activity / RNA polymerase II CTD heptapeptide repeat T4 kinase activity / RNA polymerase II CTD heptapeptide repeat S5 kinase activity ...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 / RNA polymerase II CTD heptapeptide repeat Y1 kinase activity / RNA polymerase II CTD heptapeptide repeat S2 kinase activity / RNA polymerase II CTD heptapeptide repeat T4 kinase activity / RNA polymerase II CTD heptapeptide repeat S5 kinase activity / RNA polymerase II CTD heptapeptide repeat S7 kinase activity / 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 / cyclin-dependent protein serine/threonine kinase activity / Formation of HIV elongation complex in the absence of HIV Tat / 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 / positive regulation of transcription elongation by RNA polymerase II / TP53 Regulates Transcription of DNA Repair Genes / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / mRNA processing / protein autophosphorylation / transcription by RNA polymerase II / protein kinase activity / nuclear speck / cell division / protein serine kinase activity / DNA damage response / protein kinase binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus
Similarity search - Function
Cyclin-T2-like, C-terminal domain / Cyclin/Cyclin-like subunit Ssn8 / Cyclin, C-terminal domain / Cyclin_C / Cyclin-like / Cyclin A; domain 1 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma ...Cyclin-T2-like, C-terminal domain / Cyclin/Cyclin-like subunit Ssn8 / Cyclin, C-terminal domain / Cyclin_C / 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 / : / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-8M1 / Cyclin-K / Cyclin-dependent kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsKlein, M.G.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of 3-Benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors.
Authors: Ito, M. / Tanaka, T. / Toita, A. / Uchiyama, N. / Kokubo, H. / Morishita, N. / Klein, M.G. / Zou, H. / Murakami, M. / Kondo, M. / Sameshima, T. / Araki, S. / Endo, S. / Kawamoto, T. / Morin, ...Authors: Ito, M. / Tanaka, T. / Toita, A. / Uchiyama, N. / Kokubo, H. / Morishita, N. / Klein, M.G. / Zou, H. / Murakami, M. / Kondo, M. / Sameshima, T. / Araki, S. / Endo, S. / Kawamoto, T. / Morin, G.B. / Aparicio, S.A. / Nakanishi, A. / Maezaki, H. / Imaeda, Y.
History
DepositionMar 1, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 29, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_conn_type / struct_ncs_dom_lim
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 / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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)145,3429
Polymers144,3884
Non-polymers9545
Water68538
1
A: Cyclin-dependent kinase 12
B: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,6835
Polymers72,1942
Non-polymers4893
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1810 Å2
ΔGint-17 kcal/mol
Surface area24740 Å2
MethodPISA
2
C: Cyclin-dependent kinase 12
D: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,6594
Polymers72,1942
Non-polymers4652
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1730 Å2
ΔGint-12 kcal/mol
Surface area24830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.596, 107.530, 138.324
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
12B
22D

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ARGARGGLUGLUAA722 - 102410 - 312
21ARGARGGLUGLUCC722 - 102410 - 312
12PROPROSERSERBB22 - 25923 - 260
22PROPROSERSERDD22 - 25923 - 260

NCS ensembles :
ID
1
2

-
Components

#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: 40764.992 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 713-1062
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK12, CRK7, CRKRS, KIAA0904 / Production host: unidentified baculovirus
References: UniProt: Q9NYV4, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein Cyclin-K


Mass: 31429.172 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 1-267
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNK, CPR4 / Production host: unidentified baculovirus / References: UniProt: O75909
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-8M1 / N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-N-{trans-4-[(quinazolin-2-yl)amino]cyclohexyl}acetamide


Mass: 440.540 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28N6O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.49 Å3/Da / Density % sol: 50.56 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES (PH 6.5), 18% PEG 3350, 0.2 M MGCL2, AND 1 MM SARCOSINE, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 297K

-
Data collection

DiffractionMean temperature: 173 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.75→50 Å / Num. obs: 38257 / % possible obs: 99.9 % / Redundancy: 6.9 % / Net I/σ(I): 13.9
Reflection shellResolution: 2.75→2.8 Å

-
Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
REFMAC5.7.0025refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→45.64 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.933 / SU B: 32.146 / SU ML: 0.279 / Cross valid method: THROUGHOUT / ESU R Free: 0.361 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.251 1813 5 %RANDOM
Rwork0.208 ---
obs0.21 34375 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 85.84 Å2
Baniso -1Baniso -2Baniso -3
1--1.84 Å20 Å20 Å2
2--4.36 Å20 Å2
3----2.52 Å2
Refinement stepCycle: LAST / Resolution: 2.8→45.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8613 0 69 38 8720
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0198895
X-RAY DIFFRACTIONr_bond_other_d0.0030.028408
X-RAY DIFFRACTIONr_angle_refined_deg1.3741.97412046
X-RAY DIFFRACTIONr_angle_other_deg0.925319331
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.03351056
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.90323.768414
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.073151549
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5641555
X-RAY DIFFRACTIONr_chiral_restr0.0750.21313
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0219893
X-RAY DIFFRACTIONr_gen_planes_other0.0030.022070
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A180980.08
12C180980.08
21B149230.06
22D149230.06
LS refinement shellResolution: 2.8→2.87 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.361 137 -
Rwork0.318 2506 -
obs--99.96 %
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)
13.80220.052-2.97171.2944-0.88237.1510.055-0.1630.1744-0.00850.14860.0417-0.0609-0.801-0.20360.1062-0.0151-0.0340.2926-0.01140.21322.6083-18.229533.5559
23.67011.1141-1.83113.3435-0.85743.77380.3333-0.21570.4860.156-0.0863-0.2476-0.5597-0.2252-0.2470.11320.03130.04340.0537-0.02340.146541.8432-16.174666.9862
33.23670.0152-1.57161.55560.10286.68610.05730.33890.2946-0.11920.0173-0.1227-0.31970.7989-0.07460.1441-0.0494-0.04640.19370.03420.2191-22.9989-14.464135.6695
45.1136-2.7595-0.30165.55990.18833.23380.10410.3137-0.1587-0.1073-0.06960.3635-0.09790.3699-0.03440.0973-0.050.03510.0898-0.03130.0731-42.627-15.17772.0833
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A722 - 1024
2X-RAY DIFFRACTION1A1101 - 1102
3X-RAY DIFFRACTION2B22 - 259
4X-RAY DIFFRACTION3C722 - 1024
5X-RAY DIFFRACTION3C1101 - 1102
6X-RAY DIFFRACTION4D22 - 259

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more