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- PDB-7nwk: Crystal structure of CDK9-Cyclin T1 bound by compound 6 -

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Basic information

Entry
Database: PDB / ID: 7nwk
TitleCrystal structure of CDK9-Cyclin T1 bound by compound 6
Components
  • Cyclin-T1
  • Cyclin-dependent kinase 9
KeywordsTRANSFERASE / inhibitor / kinase
Function / homology
Function and homology information


P-TEFb complex / Interactions of Tat with host cellular proteins / nucleus localization / 7SK snRNA binding / cyclin/CDK positive transcription elongation factor complex / regulation of muscle cell differentiation / regulation of mRNA 3'-end processing / positive regulation of protein localization to chromatin / RNA polymerase II CTD heptapeptide repeat Y1 kinase activity / RNA polymerase II CTD heptapeptide repeat S2 kinase activity ...P-TEFb complex / Interactions of Tat with host cellular proteins / nucleus localization / 7SK snRNA binding / cyclin/CDK positive transcription elongation factor complex / regulation of muscle cell differentiation / regulation of mRNA 3'-end processing / positive regulation of protein localization to chromatin / 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 / transcription elongation factor activity / cyclin-dependent protein serine/threonine kinase activator activity / positive regulation by host of viral transcription / positive regulation of DNA-templated transcription, elongation / RNA polymerase binding / [RNA-polymerase]-subunit kinase / negative regulation of protein localization to chromatin / regulation of cyclin-dependent protein serine/threonine kinase activity / transcription elongation-coupled chromatin remodeling / cellular response to cytokine stimulus / replication fork processing / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / RNA polymerase II transcribes snRNA genes / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / cyclin-dependent kinase / Tat-mediated elongation of the HIV-1 transcript / cyclin-dependent protein serine/threonine kinase activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / regulation of DNA repair / 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 / transcription elongation factor complex / positive regulation of transcription elongation by RNA polymerase II / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / molecular condensate scaffold activity / transcription coactivator binding / PML body / cytoplasmic ribonucleoprotein granule / kinase activity / DNA-binding transcription factor binding / Estrogen-dependent gene expression / transcription by RNA polymerase II / cell population proliferation / protein kinase activity / transcription cis-regulatory region binding / regulation of cell cycle / protein phosphorylation / RNA polymerase II cis-regulatory region sequence-specific DNA binding / response to xenobiotic stimulus / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / chromatin binding / protein kinase binding / positive regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / ATP binding / nucleus / membrane / cytosol
Similarity search - Function
: / Cyclin-T2-like, C-terminal domain / Cyclin/Cyclin-like subunit Ssn8 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / : / Serine/threonine-protein kinase, active site ...: / Cyclin-T2-like, C-terminal domain / Cyclin/Cyclin-like subunit Ssn8 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / : / 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-UT5 / Cyclin-T1 / Cyclin-dependent kinase 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.81 Å
AuthorsCollie, G.W. / Ferguson, A.D.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement.
Authors: Barlaam, B. / De Savi, C. / Dishington, A. / Drew, L. / Ferguson, A.D. / Ferguson, D. / Gu, C. / Hande, S. / Hassall, L. / Hawkins, J. / Hird, A.W. / Holmes, J. / Lamb, M.L. / Lister, A.S. / ...Authors: Barlaam, B. / De Savi, C. / Dishington, A. / Drew, L. / Ferguson, A.D. / Ferguson, D. / Gu, C. / Hande, S. / Hassall, L. / Hawkins, J. / Hird, A.W. / Holmes, J. / Lamb, M.L. / Lister, A.S. / McGuire, T.M. / Moore, J.E. / O'Connell, N. / Patel, A. / Pike, K.G. / Sarkar, U. / Shao, W. / Stead, D. / Varnes, J.G. / Vasbinder, M.M. / Wang, L. / Wu, L. / Xue, L. / Yang, B. / Yao, T.
History
DepositionMar 16, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 27, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 10, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-dependent kinase 9
B: Cyclin-T1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,3653
Polymers67,9962
Non-polymers3681
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1740 Å2
ΔGint-12 kcal/mol
Surface area26720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)172.880, 172.880, 98.310
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Cyclin-dependent kinase 9 / C-2K / Cell division cycle 2-like protein kinase 4 / Cell division protein kinase 9 / ...C-2K / Cell division cycle 2-like protein kinase 4 / Cell division protein kinase 9 / Serine/threonine-protein kinase PITALRE / Tat-associated kinase complex catalytic subunit


Mass: 38031.113 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK9, CDC2L4, TAK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P50750, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein Cyclin-T1 / CycT1 / Cyclin-T


Mass: 29965.258 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNT1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O60563
#3: Chemical ChemComp-UT5 / N-((1R,3R)-3-(7-(4-fluoro-2-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentyl)acetamide / ~{N}-[(1~{R},3~{R})-3-[7-(4-fluoranyl-2-methoxy-phenyl)-1~{H}-imidazo[4,5-b]pyridin-2-yl]cyclopentyl]ethanamide


Mass: 368.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21FN4O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: 4.16 Å3/Da / Density % sol: 70.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 14% PEG1000, 100 mM sodium potassium phosphate, pH 6.2, 500 mM NaCl, 4 mM TCEP

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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: Nov 4, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.81→86.44 Å / Num. obs: 26767 / % possible obs: 99.9 % / Redundancy: 4.3 % / Biso Wilson estimate: 81.3 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.051 / Rrim(I) all: 0.108 / Net I/σ(I): 13 / Num. measured all: 116117
Reflection shellResolution: 2.81→3.14 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.67 / Mean I/σ(I) obs: 2.8 / Num. measured all: 1171 / Num. unique obs: 261 / CC1/2: 0.683 / Rpim(I) all: 0.354 / Rrim(I) all: 0.759 / Net I/σ(I) obs: 2.4 / % possible all: 99.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimlessdata scaling
PHASERphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal

Resolution: 2.81→32.77 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.355 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.316 / SU Rfree Blow DPI: 0.222 / SU Rfree Cruickshank DPI: 0.234
RfactorNum. reflection% reflectionSelection details
Rfree0.205 1344 5.04 %RANDOM
Rwork0.18 ---
obs0.182 26685 100 %-
Displacement parametersBiso max: 161.97 Å2 / Biso mean: 66.17 Å2 / Biso min: 24.99 Å2
Baniso -1Baniso -2Baniso -3
1-0.7169 Å20 Å20 Å2
2--0.7169 Å20 Å2
3----1.4338 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.81→32.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4408 0 27 0 4435
Biso mean--55.46 --
Num. residues----550
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1569SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes775HARMONIC5
X-RAY DIFFRACTIONt_it4537HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion586SEMIHARMONIC5
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_contact5129SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4537HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6164HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion3.01
X-RAY DIFFRACTIONt_other_torsion18.39
LS refinement shellResolution: 2.81→2.83 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3186 25 4.68 %
Rwork0.2354 509 -
all0.2391 534 -
obs--100 %
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)
11.8975-0.2911-0.48951.8262-0.65933.4806-0.2831-0.08730.19850.4280.32150.2903-0.2682-0.5788-0.0385-0.09510.07810.0337-0.13470.0376-0.057-39.236-32.82188.1044
23.29460.83940.15592.3770.41681.81950.0177-0.15-0.36470.05090.0513-0.11870.12860.0796-0.069-0.1309-0.05450.0131-0.20950.0797-0.1378-7.6059-20.4136-10.3646
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A7 - 326
2X-RAY DIFFRACTION2{ B|* }B8 - 259

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