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- PDB-6p8f: Crystal structure of CDK4 in complex with CyclinD1 and P27 -

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Basic information

Entry
Database: PDB / ID: 6p8f
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 / 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 / autophagic cell death / RUNX3 regulates WNT signaling / response to leptin / FOXO-mediated transcription of cell cycle genes / negative regulation of epithelial cell proliferation involved in prostate gland development / positive regulation of mammary gland epithelial cell proliferation / regulation of cell cycle G1/S phase transition / regulation of exit from mitosis / cellular response to phorbol 13-acetate 12-myristate / Transcriptional regulation by RUNX2 / epithelial cell proliferation involved in prostate gland development / negative regulation of epithelial cell apoptotic process / negative regulation of cyclin-dependent protein serine/threonine kinase activity / ubiquitin ligase activator activity / negative regulation of phosphorylation / cyclin-dependent protein serine/threonine kinase inhibitor activity / RHO GTPases activate CIT / nuclear export / cyclin-dependent protein serine/threonine kinase activator activity / proline-rich region binding / Regulation of RUNX1 Expression and Activity / AKT phosphorylates targets in the cytosol / cyclin-dependent protein serine/threonine kinase regulator activity / Cul4A-RING E3 ubiquitin ligase complex / mammary gland epithelial cell proliferation / response to UV-A / epithelial cell apoptotic process / cellular response to antibiotic / negative regulation of epithelial cell differentiation / negative regulation of kinase activity / regulation of cyclin-dependent protein serine/threonine kinase activity / molecular function inhibitor activity / cellular response to lithium ion / protein kinase inhibitor activity / fat cell differentiation / p53-Dependent G1 DNA Damage Response / PTK6 Regulates Cell Cycle / Constitutive Signaling by AKT1 E17K in Cancer / regulation of G1/S transition of mitotic cell cycle / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / negative regulation of vascular associated smooth muscle cell proliferation / inner ear development / RUNX3 regulates p14-ARF / cellular response to organic cyclic compound / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / Transcriptional Regulation by VENTX / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / cyclin-dependent protein kinase holoenzyme complex / bicellular tight junction / localization / mammary gland alveolus development / response to amino acid / positive regulation of G1/S transition of mitotic cell cycle / cyclin-dependent kinase / cellular response to interleukin-4 / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / response to glucose / Cyclin E associated events during G1/S transition / response to cadmium ion / Cyclin A:Cdk2-associated events at S phase entry / endoplasmic reticulum unfolded protein response / Notch signaling pathway / regulation of cell migration / positive regulation of microtubule polymerization / mitotic G1 DNA damage checkpoint signaling / regulation of G2/M transition of mitotic cell cycle / Hsp70 protein binding / positive regulation of G2/M transition of mitotic cell cycle / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / FLT3 Signaling / lactation / transcription repressor complex / cyclin binding / : / positive regulation of DNA replication / Ubiquitin-dependent degradation of Cyclin D / liver regeneration / sensory perception of sound / potassium ion transport / placenta development / neuron differentiation / 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: 2.89 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)72,1903
Polymers72,1903
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6280 Å2
ΔGint-43 kcal/mol
Surface area27050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.855, 66.628, 184.240
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: 9796.787 Da / Num. of mol.: 1
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
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: 2.67 Å3/Da / Density % sol: 58.97 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 100mM Tris (7.0) 17% PEG 3350 100 mM CaCl2 10 mM MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 8, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.89→46.06 Å / Num. obs: 18044 / % possible obs: 99.8 % / Redundancy: 12.9 % / Rmerge(I) obs: 0.18 / Rpim(I) all: 0.056 / Net I/σ(I): 14.3
Reflection shellResolution: 2.89→3.07 Å / Redundancy: 12.8 % / Rmerge(I) obs: 0.99 / Mean I/σ(I) obs: 2.9 / Num. unique obs: 2830 / CC1/2: 0.81 / Rpim(I) all: 0.296

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.89→46.06 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 24.02
RfactorNum. reflection% reflection
Rfree0.2422 848 4.88 %
Rwork0.1862 --
obs0.189 17381 96.38 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.89→46.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4498 0 0 0 4498
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044597
X-RAY DIFFRACTIONf_angle_d0.6556223
X-RAY DIFFRACTIONf_dihedral_angle_d6.4772832
X-RAY DIFFRACTIONf_chiral_restr0.04694
X-RAY DIFFRACTIONf_plane_restr0.005805
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.89-3.0710.31191320.23012516X-RAY DIFFRACTION90
3.071-3.30810.28491130.25112679X-RAY DIFFRACTION95
3.3081-3.64080.26521400.20332716X-RAY DIFFRACTION97
3.6408-4.16740.2631550.1762790X-RAY DIFFRACTION98
4.1674-5.24930.20711490.15292845X-RAY DIFFRACTION99
5.2493-46.06580.2141590.17822987X-RAY DIFFRACTION99
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)
10.15950.791-0.27525.84912.67898.42490.8512-0.199-1.85050.58311.2939-0.59181.2617-0.4584-1.2560.8266-0.0527-0.19240.49140.1321.14859.0577-37.646-24.0655
27.51144.45764.19865.03311.48547.60921.4313-0.5065-1.25350.40930.1033-0.50263.0668-0.4165-1.11221.0669-0.0375-0.49010.72970.17861.38612.3166-38.5002-19.0601
39.24596.06683.97874.41951.32199.43130.8859-0.65750.00690.5747-1.1319-1.32420.16770.61410.14160.2827-0.0366-0.08920.48480.05090.520916.33-5.5117-39.5542
45.5724-1.67450.05714.80160.59864.54260.10650.13190.1922-0.37360.0546-0.29780.06230.3138-0.12270.2174-0.05750.01930.14950.02270.2469-3.5944-21.1318-49.3378
53.81870.12970.16372.57981.94662.9564-0.025-0.0238-0.46480.22730.08190.27810.2531-0.1351-0.02260.22070.0162-0.00380.14860.05290.3697-7.9847-24.7051-39.9566
64.27881.2517-1.18312.11970.31520.6865-0.0499-0.20160.42120.59520.2902-0.1051-0.08970.1329-0.25440.2361-0.0377-0.00590.2728-0.02470.29185.92180.9912-44.5661
74.93513.48312.29199.28436.22957.8487-0.1336-0.13320.36920.62650.03370.4869-0.0551-0.38540.24250.23340.00460.07070.28390.04620.2706-2.7536-0.849-50.1293
85.036-0.42850.37717.15381.59140.35580.00240.61440.0206-0.7149-0.0077-0.06550.2146-0.35210.00940.3668-0.0470.0320.35860.00120.15994.0615-7.3775-55.3567
91.2271-0.12510.28110.0067-0.0570.0945-0.6650.51230.8733-1.5233-0.58541.684-0.6798-0.54830.11980.75020.2245-0.56750.2510.32750.96122.850111.2977-57.5672
108.4477-5.25083.37218.8308-5.28369.96540.26830.1875-0.9842-0.57820.1229-0.4312-0.02810.9103-0.40610.2768-0.0288-0.01080.298-0.0550.386415.28660.674-53.8556
114.14432.87264.18616.03021.80338.10240.03821.9263-1.2504-0.54960.4668-0.09240.40810.5091-0.32880.4782-0.03820.01690.4035-0.03760.30880.0185-7.8554-62.816
124.1514-2.80144.89875.1925-1.77315.8722-0.0885-0.558-0.8750.9020.1638-0.5159-0.0529-0.0764-0.19580.5503-0.0447-0.07540.44950.03390.53976.6028-25.8064-24.3192
134.10411.76531.15343.79331.04442.35580.3486-0.3096-0.51810.7208-0.0524-0.15580.59840.0119-0.32870.52190.0076-0.06730.38210.03910.291618.6554-16.443-18.9294
141.13650.5722-1.67355.48473.51596.21620.43320.06010.37250.7691-0.95951.5360.4721-1.1582-0.25270.5371-0.07630.17470.89660.09780.33148.3174-6.5264-13.098
156.4875-0.8887-0.30153.24813.01385.53460.4161-1.3044-0.05581.0641-0.06830.5219-0.47860.0577-0.21480.82370.01040.19630.58940.06460.327916.4888-1.5167-5.9611
165.95740.01583.7824.4213-1.61333.91630.27650.04582.0909-0.7225-0.3330.8668-0.6895-0.6946-0.07611.11980.3030.3090.8745-0.01390.7313.794911.7439-9.823
178.3-2.8406-4.23094.87633.86637.63340.5553-0.54040.86021.00730.2495-0.1552-0.98590.4056-0.7190.8415-0.08250.18520.39730.00720.47619.76696.8943-9.5219
180.54881.46-0.62335.521.74017.86880.31880.27970.1829-0.66310.3069-0.7674-0.05590.6555-0.32980.45520.04140.10840.51420.09250.296829.7767-0.3121-23.3829
192.22672.4632-1.27613.3588-2.88814.31040.13510.0277-0.56920.40.23391.4039-0.0548-0.7077-0.10680.2653-0.0373-0.06690.5012-0.07320.8392-19.7781-25.8238-49.9524
204.185-1.12194.16340.2949-1.22644.41641.0145-0.0112-2.0481.294-0.0797-0.44991.42120.0191-0.9020.86380.1419-0.30380.4378-0.13181.0025-2.4808-39.7297-36.103
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN C AND RESID 60:64 )C60 - 64
2X-RAY DIFFRACTION2( CHAIN C AND RESID 65:79 )C65 - 79
3X-RAY DIFFRACTION3( CHAIN A AND RESID 21:36 )A21 - 36
4X-RAY DIFFRACTION4( CHAIN A AND RESID 37:89 )A37 - 89
5X-RAY DIFFRACTION5( CHAIN A AND RESID 90:156 )A90 - 156
6X-RAY DIFFRACTION6( CHAIN A AND RESID 157:171 )A157 - 171
7X-RAY DIFFRACTION7( CHAIN A AND RESID 172:191 )A172 - 191
8X-RAY DIFFRACTION8( CHAIN A AND RESID 192:216 )A192 - 216
9X-RAY DIFFRACTION9( CHAIN A AND RESID 217:225 )A217 - 225
10X-RAY DIFFRACTION10( CHAIN A AND RESID 226:240 )A226 - 240
11X-RAY DIFFRACTION11( CHAIN A AND RESID 241:264 )A241 - 264
12X-RAY DIFFRACTION12( CHAIN B AND RESID 18:62 )B18 - 62
13X-RAY DIFFRACTION13( CHAIN B AND RESID 63:151 )B63 - 151
14X-RAY DIFFRACTION14( CHAIN B AND RESID 152:190 )B152 - 190
15X-RAY DIFFRACTION15( CHAIN B AND RESID 191:227 )B191 - 227
16X-RAY DIFFRACTION16( CHAIN B AND RESID 228:242 )B228 - 242
17X-RAY DIFFRACTION17( CHAIN B AND RESID 243:282 )B243 - 282
18X-RAY DIFFRACTION18( CHAIN B AND RESID 283:296 )B283 - 296
19X-RAY DIFFRACTION19( CHAIN C AND RESID 24:37 )C24 - 37
20X-RAY DIFFRACTION20( CHAIN C AND RESID 38:59 )C38 - 59

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