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- PDB-6p8h: Crystal structure of CDK4 in complex with CyclinD1 and P21 -

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Basic information

Entry
Database: PDB / ID: 6p8h
TitleCrystal structure of CDK4 in complex with CyclinD1 and P21
Components
  • Cyclin-dependent kinase 4
  • Cyclin-dependent kinase inhibitor 1
  • G1/S-specific cyclin-D1
Keywordscell cycle / transferase / Cyclin-dependent kinase / kinase inhibitor
Function / homology
Function and homology information


: / 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 cyclin-dependent protein kinase activity / negative regulation of cardiac muscle tissue regeneration / cyclin D1-CDK6 complex / re-entry into mitotic cell cycle ...: / 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 cyclin-dependent protein kinase activity / negative regulation of cardiac muscle tissue regeneration / cyclin D1-CDK6 complex / re-entry into mitotic cell cycle / regulation of transcription initiation by RNA polymerase II / 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 / Drug-mediated inhibition of CDK4/CDK6 activity / negative regulation of DNA biosynthetic process / regulation of type B pancreatic cell proliferation / RUNX3 regulates WNT signaling / FOXO-mediated transcription of cell cycle genes / TFAP2 (AP-2) family regulates transcription of cell cycle factors / positive regulation of mammary gland epithelial cell proliferation / cellular response to cell-matrix adhesion / response to leptin / cellular response to ionomycin / PCNA-p21 complex / regulation of cell cycle G1/S phase transition / import into nucleus / Transcriptional regulation by RUNX2 / Leydig cell differentiation / tissue regeneration / cellular response to phorbol 13-acetate 12-myristate / cyclin-dependent protein serine/threonine kinase inhibitor activity / proline-rich region binding / cyclin-dependent protein serine/threonine kinase activator activity / oncogene-induced cell senescence / Transcriptional activation of cell cycle inhibitor p21 / Regulation of RUNX1 Expression and Activity / positive regulation of programmed cell death / AKT phosphorylates targets in the cytosol / response to iron ion / RUNX3 regulates CDKN1A transcription / stress-induced premature senescence / mammary gland epithelial cell proliferation / cyclin-dependent protein serine/threonine kinase regulator activity / response to UV-A / molecular function inhibitor activity / cellular response to UV-B / response to corticosterone / response to vitamin E / STAT5 activation downstream of FLT3 ITD mutants / negative regulation of epithelial cell differentiation / negative regulation of G1/S transition of mitotic cell cycle / p53-Dependent G1 DNA Damage Response / Constitutive Signaling by AKT1 E17K in Cancer / PTK6 Regulates Cell Cycle / fat cell differentiation / mitotic G2 DNA damage checkpoint signaling / protein kinase inhibitor activity / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / positive regulation of protein kinase activity / microtubule organizing center / negative regulation of vascular associated smooth muscle cell proliferation / regulation of G1/S transition of mitotic cell cycle / Transcriptional Regulation by VENTX / response to magnesium ion / replicative senescence / RUNX3 regulates p14-ARF / keratinocyte proliferation / mammary gland alveolus development / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G2/M transition of mitotic cell cycle / bicellular tight junction / response to X-ray / positive regulation of G1/S transition of mitotic cell cycle / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cyclin E associated events during G1/S transition / endoplasmic reticulum unfolded protein response / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / keratinocyte differentiation / regulation of G2/M transition of mitotic cell cycle / lactation / positive regulation of B cell proliferation / mitotic G1 DNA damage checkpoint signaling / transcription repressor complex / Signaling by FLT3 fusion proteins / liver regeneration / cellular response to interleukin-4 / intrinsic apoptotic signaling pathway / protein serine/threonine kinase binding / cyclin binding / protein sequestering activity / cellular response to amino acid starvation / molecular function activator activity / positive regulation of DNA replication / protein serine/threonine kinase activator activity / cellular response to ionizing radiation
Similarity search - Function
Cyclin-dependent kinase inhibitor 1 / Cyclin-dependent kinase inhibitor domain / Cyclin-dependent kinase inhibitor domain superfamily / Cyclin-dependent kinase inhibitor / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin-like / Cyclin, C-terminal domain ...Cyclin-dependent kinase inhibitor 1 / Cyclin-dependent kinase inhibitor domain / Cyclin-dependent kinase inhibitor domain superfamily / Cyclin-dependent kinase inhibitor / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin-like / Cyclin, C-terminal domain / Cyclin_C / 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 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.19 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 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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 1


Theoretical massNumber of molelcules
Total (without water)71,4803
Polymers71,4803
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5930 Å2
ΔGint-45 kcal/mol
Surface area25990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.620, 67.980, 185.360
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
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 1 / CDK-interacting protein 1 / Melanoma differentiation-associated protein 6 / MDA-6 / p21


Mass: 9087.271 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDKN1A, CAP20, CDKN1, CIP1, MDA6, PIC1, SDI1, WAF1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P38936

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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: 2.76 Å3/Da / Density % sol: 55.43 %
Crystal growTemperature: 295 K / Method: microbatch / pH: 7 / Details: 100mM Tris (7.0), 10% PEG 8000 200mM MgCl2

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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: Dec 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.19→92.68 Å / Num. obs: 13821 / % possible obs: 99.9 % / Redundancy: 5.9 % / CC1/2: 0.99 / Rmerge(I) obs: 0.167 / Rpim(I) all: 0.08 / Net I/σ(I): 9.2
Reflection shellResolution: 3.19→3.41 Å / Redundancy: 5.8 % / Mean I/σ(I) obs: 2.1 / Num. unique obs: 2439 / CC1/2: 0.75 / Rpim(I) all: 0.406 / Rsym value: 0.837 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX(1.15.2_3472: ???)refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2W96

2w96


Resolution: 3.19→44.698 Å / SU ML: 0.43 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.1 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2575 721 5.24 %
Rwork0.2056 --
obs0.2084 13772 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.19→44.698 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4388 0 0 0 4388
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024477
X-RAY DIFFRACTIONf_angle_d0.4926062
X-RAY DIFFRACTIONf_dihedral_angle_d7.922761
X-RAY DIFFRACTIONf_chiral_restr0.037687
X-RAY DIFFRACTIONf_plane_restr0.004787
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1902-3.43650.35071340.28682544X-RAY DIFFRACTION100
3.4365-3.78210.27051390.22742568X-RAY DIFFRACTION100
3.7821-4.3290.28181310.20012591X-RAY DIFFRACTION100
4.329-5.45260.25251480.18472613X-RAY DIFFRACTION100
5.4526-44.70260.21751690.18732735X-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)
12.2054-0.0317-0.65644.0958-0.79194.18520.1922-0.05030.4364-0.06850.029-0.1504-0.4756-0.2248-0.20580.37360.01840.06080.3869-0.03720.43134.3608-13.3318-43.5482
25.20813.8424-2.55378.1149-0.84744.7082-0.03740.53440.0146-0.35750.08480.07880.0781-0.0991-0.01870.29490.0604-0.03690.52470.07430.357427.1216-31.8453-54.3308
35.03342.173-1.99962.7979-1.76852.55520.5824-0.45330.69420.5404-0.12290.4789-0.6511-0.4479-0.44480.59630.03090.11270.6499-0.1270.481317.2322-15.0266-20.7964
45.1444-0.31251.77347.546-2.23237.2320.3582-0.4214-0.32530.7957-0.1627-0.30150.4268-0.2723-0.16780.6045-0.0123-0.10780.6518-0.03410.361615.8516-36.5557-10.6482
51.62220.58950.89186.97662.36712.7670.1249-0.18520.3022-0.92190.9051-0.7065-0.61680.9834-0.7340.6643-0.13010.43171.19950.14920.983549.6064-8.0391-50.9608
60.95950.4958-0.67160.4918-1.00482.29930.0439-0.39941.10430.82150.0336-0.057-0.9799-0.1920.13391.33740.07930.2960.583-0.20771.563326.88365.1752-28.7069
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 19:156 )A19 - 156
2X-RAY DIFFRACTION2( CHAIN A AND RESID 157:262 )A157 - 262
3X-RAY DIFFRACTION3( CHAIN B AND RESID 18:153 )B18 - 153
4X-RAY DIFFRACTION4( CHAIN B AND RESID 154:295 )B154 - 295
5X-RAY DIFFRACTION5( CHAIN C AND RESID 14:15 )C14 - 15
6X-RAY DIFFRACTION6( CHAIN C AND RESID 16:56 )C16 - 56

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