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- PDB-6p8g: Crystal structure of CDK4 in complex with CyclinD1 and P27 -

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Basic information

Entry
Database: PDB / ID: 6p8g
TitleCrystal structure of CDK4 in complex with CyclinD1 and P27
Components
  • Cyclin-dependent kinase 4
  • Cyclin-dependent kinase inhibitor 1B
  • G1/S-specific cyclin-D1
Keywordscell cycle / transferase / Cyclin-dependent kinase / kinase inhibitor
Function / homology
Function and homology information


re-entry into mitotic cell cycle / cyclin-dependent protein kinase activating kinase regulator activity / regulation of lens fiber cell differentiation / cyclin D3-CDK4 complex / cyclin D1-CDK4 complex / cyclin D2-CDK4 complex / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 / Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 / negative regulation of cardiac muscle tissue regeneration / negative regulation of cyclin-dependent protein kinase activity ...re-entry into mitotic cell cycle / cyclin-dependent protein kinase activating kinase regulator activity / regulation of lens fiber cell differentiation / cyclin D3-CDK4 complex / cyclin D1-CDK4 complex / cyclin D2-CDK4 complex / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 / Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 / negative regulation of cardiac muscle tissue regeneration / negative regulation of cyclin-dependent protein kinase activity / cellular response to ionomycin / autophagic cell death / regulation of transcription initiation by RNA polymerase II / Drug-mediated inhibition of CDK4/CDK6 activity / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 / Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 / regulation of type B pancreatic cell proliferation / RUNX3 regulates WNT signaling / response to leptin / negative regulation of epithelial cell proliferation involved in prostate gland development / FOXO-mediated transcription of cell cycle genes / positive regulation of mammary gland epithelial cell proliferation / regulation of cell cycle G1/S phase transition / regulation of exit from mitosis / Transcriptional regulation by RUNX2 / cellular response to phorbol 13-acetate 12-myristate / epithelial cell proliferation involved in prostate gland development / negative regulation of phosphorylation / mitotic cell cycle phase transition / negative regulation of epithelial cell apoptotic process / negative regulation of cyclin-dependent protein serine/threonine kinase activity / ubiquitin ligase activator activity / cyclin-dependent protein serine/threonine kinase inhibitor activity / RHO GTPases activate CIT / cyclin-dependent protein serine/threonine kinase activator activity / nuclear export / proline-rich region binding / Regulation of RUNX1 Expression and Activity / AKT phosphorylates targets in the cytosol / cyclin-dependent protein serine/threonine kinase regulator activity / mammary gland epithelial cell proliferation / Cul4A-RING E3 ubiquitin ligase complex / response to UV-A / epithelial cell apoptotic process / cellular response to antibiotic / negative regulation of kinase activity / negative regulation of epithelial cell differentiation / molecular function inhibitor activity / protein kinase inhibitor activity / cellular response to lithium ion / fat cell differentiation / p53-Dependent G1 DNA Damage Response / PTK6 Regulates Cell Cycle / regulation of cyclin-dependent protein serine/threonine kinase activity / regulation of G1/S transition of mitotic cell cycle / Constitutive Signaling by AKT1 E17K in Cancer / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / inner ear development / negative regulation of vascular associated smooth muscle cell proliferation / RUNX3 regulates p14-ARF / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / Transcriptional Regulation by VENTX / cellular response to organic cyclic compound / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / cyclin-dependent protein kinase holoenzyme complex / bicellular tight junction / mammary gland alveolus development / response to amino acid / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / localization / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / response to glucose / response to cadmium ion / Cyclin E associated events during G1/S transition / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / endoplasmic reticulum unfolded protein response / Cyclin A:Cdk2-associated events at S phase entry / positive regulation of microtubule polymerization / regulation of cell migration / Notch signaling pathway / Hsp70 protein binding / mitotic G1 DNA damage checkpoint signaling / positive regulation of G2/M transition of mitotic cell cycle / regulation of G2/M transition of mitotic cell cycle / transcription repressor complex / cellular response to interleukin-4 / lactation / FLT3 Signaling / cyclin binding / placenta development / positive regulation of DNA replication / response to organic substance / Ubiquitin-dependent degradation of Cyclin D / liver regeneration / sensory perception of sound / G1/S transition of mitotic cell cycle / potassium ion transport / Oncogene Induced Senescence
Similarity search - Function
Cyclin-dependent kinase inhibitor domain / Cyclin-dependent kinase inhibitor domain superfamily / Cyclin-dependent kinase inhibitor / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin-like ...Cyclin-dependent kinase inhibitor domain / Cyclin-dependent kinase inhibitor domain superfamily / Cyclin-dependent kinase inhibitor / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / 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 / 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
Cyclin-dependent kinase 4 / G1/S-specific cyclin-D1 / Cyclin-dependent kinase inhibitor 1B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsGuiley, K.Z. / Stevenson, J.W. / Lou, K. / Barkovich, K.J. / Bunch, K. / Tripathi, S.M. / Shokat, K.M. / Rubin, S.M.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)GM124148 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA206244 United States
CitationJournal: Science / Year: 2019
Title: p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition.
Authors: Guiley, K.Z. / Stevenson, J.W. / Lou, K. / Barkovich, K.J. / Kumarasamy, V. / Wijeratne, T.U. / Bunch, K.L. / Tripathi, S. / Knudsen, E.S. / Witkiewicz, A.K. / Shokat, K.M. / Rubin, S.M.
History
DepositionJun 7, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: G1/S-specific cyclin-D1
B: Cyclin-dependent kinase 4
C: Cyclin-dependent kinase inhibitor 1B


Theoretical massNumber of molelcules
Total (without water)71,0643
Polymers71,0643
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5830 Å2
ΔGint-40 kcal/mol
Surface area26440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.580, 66.730, 184.850
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21221

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Components

#1: Protein G1/S-specific cyclin-D1 / B-cell lymphoma 1 protein / BCL-1 / BCL-1 oncogene / PRAD1 oncogene


Mass: 28445.293 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCND1, BCL1, PRAD1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24385
#2: Protein Cyclin-dependent kinase 4 / / Cell division protein kinase 4 / PSK-J3


Mass: 33947.930 Da / Num. of mol.: 1 / Mutation: G48E, G49E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P11802, cyclin-dependent kinase
#3: Protein Cyclin-dependent kinase inhibitor 1B / Cyclin-dependent kinase inhibitor p27 / p27Kip1


Mass: 8670.545 Da / Num. of mol.: 1 / Mutation: Y74E, Y88E, Y89E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDKN1B, KIP1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P46527

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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: 2.72 Å3/Da / Density % sol: 54.71 %
Crystal growTemperature: 295 K / Method: microbatch / Details: 100mM Tris (7.0) 200mM MgCl2 10% PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 30, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→92.42 Å / Num. obs: 19805 / % possible obs: 99.8 % / Redundancy: 7.1 % / Biso Wilson estimate: 38 Å2 / CC1/2: 0.98 / Rmerge(I) obs: 0.19 / Rpim(I) all: 0.07 / Net I/σ(I): 8.3
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.82 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 2851 / CC1/2: 0.78 / Rpim(I) all: 0.31 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→66.73 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.09
RfactorNum. reflection% reflection
Rfree0.2747 968 4.91 %
Rwork0.2213 --
obs0.2239 19703 99.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.8→66.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4408 0 0 0 4408
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034501
X-RAY DIFFRACTIONf_angle_d0.526095
X-RAY DIFFRACTIONf_dihedral_angle_d7.2072773
X-RAY DIFFRACTIONf_chiral_restr0.037688
X-RAY DIFFRACTIONf_plane_restr0.004790
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8001-2.94770.28791250.25872659X-RAY DIFFRACTION100
2.9477-3.13240.30691390.26982628X-RAY DIFFRACTION100
3.1324-3.37420.29781330.2442646X-RAY DIFFRACTION100
3.3742-3.71380.30321510.24112612X-RAY DIFFRACTION99
3.7138-4.25110.24751290.2182634X-RAY DIFFRACTION99
4.2511-5.35560.29721390.18722707X-RAY DIFFRACTION100
5.3556-66.7490.22951520.20372849X-RAY DIFFRACTION100
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)
13.23251.78132.10872.93051.78173.9610.4595-0.4736-0.52270.6192-0.1627-0.16250.58920.1218-0.3520.37990.0062-0.0420.45040.03650.290819.1719-17.117-19.4146
21.0502-0.683-0.22924.60521.9994.023-0.0692-0.216-0.18440.78120.16280.64880.2324-0.3601-0.10970.4446-0.10510.07990.58250.09960.328914.0617-7.6143-13.911
34.7094-2.3046-0.39745.0169-0.10293.39080.0714-0.58890.4090.69950.16640.872-0.5506-0.201-0.35580.97140.13210.30190.79350.01380.51199.01965.808-4.9833
46.2752-2.3232-2.90185.19170.72635.08960.6079-0.73640.94430.28490.1118-0.3506-0.77050.5262-0.62420.5323-0.13370.11850.4212-0.00860.327323.32134.7991-14.0157
54.60142.4122.20951.27691.55362.89180.4461-0.0512-1.42680.9658-0.0527-0.21541.04620.0835-0.42230.63-0.0059-0.16040.44850.06350.8153-6.08-35.6364-38.3684
61.98470.1941-1.7859.07540.66267.43461.0411-0.2187-0.98250.27090.00390.69782.1454-0.105-0.94121.1068-0.1983-0.39340.73870.36980.988111.7444-38.7865-18.4791
72.43413.6006-0.67345.92-1.08926.7541.2281-0.62610.30150.5698-0.6656-1.5063-0.29970.5897-0.38060.3212-0.0954-0.04370.67060.05450.623216.3623-5.026-39.5248
83.9057-0.74750.29443.67481.17584.37750.12820.2575-0.0475-0.2184-0.123-0.00810.08620.3823-0.00880.2267-0.0347-0.02190.1330.04860.2927-3.5922-21.2183-49.3498
93.6938-1.3684-0.76222.47251.41653.3265-0.10170.0128-0.71480.8346-0.02130.38120.5454-0.6382-0.0490.25690.1167-0.15860.10860.10160.2985-6.0904-26.0075-43.4611
102.5793-1.31961.5733.19610.88662.02180.2233-0.0914-0.49720.0879-0.1620.24640.2637-0.0273-0.07740.2884-0.01140.06770.15650.06230.3242-8.9914-24.067-37.8438
113.6235-0.27970.86971.91920.71131.7858-0.321-0.23720.11120.69030.10430.302-0.24460.33280.15190.33150.00650.02920.2521-0.0510.19965.86640.9265-44.7237
124.59940.9458-0.02747.4367-2.86741.1565-0.09840.19230.1690.01630.09630.26530.0643-0.03460.0120.30670.00580.01230.3090.00330.12150.9253-5.1516-52.1682
132.25952.1665-0.63855.44852.7893.4677-0.28870.62840.9836-0.8557-0.30150.9504-0.5117-0.52410.37660.52740.144-0.06490.36020.16370.56061.59298.7818-58.4382
144.2943-0.98730.25794.3909-6.29849.79080.16360.5588-0.5047-0.8058-0.4706-0.9510.64611.13470.24380.27090.0523-0.00910.34520.02090.324815.22110.5633-54.086
156.38822.27956.40183.08441.86257.79830.32951.7798-0.6467-0.3110.3052-0.06810.33550.6608-0.47850.54680.01210.00330.3458-0.02220.29371.3853-7.6666-62.6769
162.5611-1.29014.27271.4522-1.46766.4813-0.1692-2.8434-1.90150.35480.91430.41090.0957-1.0905-0.6680.57830.0017-0.03120.59460.20470.62275.1929-28.4793-21.2147
174.15832.3186-4.79817.4042-1.15366.11340.5264-1.3874-0.48740.0121-0.5542-0.6685-0.66650.6179-0.0490.4446-0.1178-0.0720.38060.01050.25754.7227-17.8418-29.5692
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'B' and (resid 63 through 130 )
2X-RAY DIFFRACTION2chain 'B' and (resid 131 through 206 )
3X-RAY DIFFRACTION3chain 'B' and (resid 207 through 245 )
4X-RAY DIFFRACTION4chain 'B' and (resid 246 through 296 )
5X-RAY DIFFRACTION5chain 'C' and (resid 25 through 64 )
6X-RAY DIFFRACTION6chain 'C' and (resid 65 through 79 )
7X-RAY DIFFRACTION7chain 'A' and (resid 20 through 36 )
8X-RAY DIFFRACTION8chain 'A' and (resid 37 through 89 )
9X-RAY DIFFRACTION9chain 'A' and (resid 90 through 114 )
10X-RAY DIFFRACTION10chain 'A' and (resid 115 through 156 )
11X-RAY DIFFRACTION11chain 'A' and (resid 157 through 171 )
12X-RAY DIFFRACTION12chain 'A' and (resid 172 through 212 )
13X-RAY DIFFRACTION13chain 'A' and (resid 213 through 225 )
14X-RAY DIFFRACTION14chain 'A' and (resid 226 through 240 )
15X-RAY DIFFRACTION15chain 'A' and (resid 241 through 262 )
16X-RAY DIFFRACTION16chain 'B' and (resid 18 through 47 )
17X-RAY DIFFRACTION17chain 'B' and (resid 48 through 62 )

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