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- PDB-1ung: Structural mechanism for the inhibition of CDK5-p25 by roscovitin... -

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Basic information

Entry
Database: PDB / ID: 1ung
TitleStructural mechanism for the inhibition of CDK5-p25 by roscovitine, aloisine and indirubin.
Components
  • CELL DIVISION PROTEIN KINASE 5
  • CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1
KeywordsCELL CYCLE / COMPLEX(KINASE-ACTIVATOR) / INHIBITORS / NEURODEGENERATIVE DISEASES
Function / homology
Function and homology information


superior olivary nucleus maturation / protein kinase 5 complex / acetylcholine receptor activator activity / G1 to G0 transition involved in cell differentiation / ErbB-2 class receptor binding / negative regulation of synaptic plasticity / contractile muscle fiber / Activated NTRK2 signals through CDK5 / neuron cell-cell adhesion / positive regulation of calcium ion-dependent exocytosis ...superior olivary nucleus maturation / protein kinase 5 complex / acetylcholine receptor activator activity / G1 to G0 transition involved in cell differentiation / ErbB-2 class receptor binding / negative regulation of synaptic plasticity / contractile muscle fiber / Activated NTRK2 signals through CDK5 / neuron cell-cell adhesion / positive regulation of calcium ion-dependent exocytosis / layer formation in cerebral cortex / negative regulation of axon extension / protein localization to synapse / regulation of synaptic vesicle cycle / receptor catabolic process / corpus callosum development / regulation of dendritic spine morphogenesis / cerebellar cortex formation / CRMPs in Sema3A signaling / NGF-stimulated transcription / synaptic transmission, dopaminergic / ErbB-3 class receptor binding / axon extension / calcium ion import / regulation of synaptic vesicle recycling / negative regulation of protein export from nucleus / motor neuron axon guidance / cyclin-dependent protein serine/threonine kinase activator activity / axonal fasciculation / dendrite morphogenesis / embryo development ending in birth or egg hatching / synaptic vesicle transport / regulation of neuron differentiation / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / tau-protein kinase activity / beta-tubulin binding / receptor clustering / protein kinase activator activity / central nervous system neuron development / oligodendrocyte differentiation / synaptic vesicle exocytosis / regulation of cyclin-dependent protein serine/threonine kinase activity / behavioral response to cocaine / alpha-tubulin binding / synaptic vesicle endocytosis / positive regulation of protein targeting to membrane / negative regulation of cell cycle / DARPP-32 events / cyclin-dependent protein kinase holoenzyme complex / regulation of macroautophagy / ephrin receptor signaling pathway / cyclin-dependent protein serine/threonine kinase activity / regulation of protein localization to plasma membrane / Schwann cell development / skeletal muscle tissue development / regulation of cell migration / positive regulation of microtubule polymerization / sensory perception of pain / negative regulation of protein ubiquitination / regulation of synaptic transmission, glutamatergic / synapse assembly / ionotropic glutamate receptor binding / excitatory postsynaptic potential / NPAS4 regulates expression of target genes / ionotropic glutamate receptor signaling pathway / cerebellum development / ephrin receptor binding / protein serine/threonine kinase activator activity / axonogenesis / cell-matrix adhesion / filopodium / synaptic transmission, glutamatergic / axon guidance / regulation of actin cytoskeleton organization / hippocampus development / negative regulation of proteolysis / intracellular protein transport / Hsp90 protein binding / brain development / peptidyl-threonine phosphorylation / neuron migration / regulation of synaptic plasticity / tau protein binding / neuromuscular junction / visual learning / G protein-coupled acetylcholine receptor signaling pathway / neuron differentiation / microtubule cytoskeleton organization / neuron projection development / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / rhythmic process / actin filament binding / p53 binding / presynapse / lamellipodium / cell junction / Factors involved in megakaryocyte development and platelet production / kinase activity / growth cone
Similarity search - Function
Cyclin-dependent kinase 5 activator / Cyclin-dependent kinase 5 activator protein / Cyclin-like / Cyclin A; domain 1 / 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 ...Cyclin-dependent kinase 5 activator / Cyclin-dependent kinase 5 activator protein / Cyclin-like / Cyclin A; domain 1 / 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
6-PHENYL[5H]PYRROLO[2,3-B]PYRAZINE / Cyclin-dependent kinase 5 / Cyclin-dependent kinase 5 activator 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsMapelli, M. / Crovace, C. / Massimiliano, L. / Musacchio, A.
CitationJournal: J.Med.Chem. / Year: 2005
Title: Mechanism of Cdk5/P25 Binding by Cdk Inhibitors
Authors: Mapelli, M. / Massimilinao, L. / Crovace, C. / Seeliger, M.A. / Tsai, L.-H. / Meijer, L. / Musacchio, A.
History
DepositionSep 10, 2003Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 10, 2004Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CELL DIVISION PROTEIN KINASE 5
B: CELL DIVISION PROTEIN KINASE 5
D: CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1
E: CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,6356
Polymers113,1004
Non-polymers5352
Water5,296294
1
A: CELL DIVISION PROTEIN KINASE 5
D: CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,8173
Polymers56,5502
Non-polymers2671
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3380 Å2
ΔGint-21.1 kcal/mol
Surface area19320 Å2
MethodPISA
2
B: CELL DIVISION PROTEIN KINASE 5
E: CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,8173
Polymers56,5502
Non-polymers2671
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3290 Å2
ΔGint-20.6 kcal/mol
Surface area22020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)117.724, 117.724, 156.794
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein CELL DIVISION PROTEIN KINASE 5 / / TAU PROTEIN KINASE II / TPKII CATALYTIC / SERINE/THREONINE PROTEIN KINASE PSSALRE / CYCLIN-DEPENDENT KINASE 5


Mass: 33349.477 Da / Num. of mol.: 2 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q00535, cyclin-dependent kinase
#2: Protein CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1 / CDK5 ACTIVATOR 1 / CYCLIN-DEPENDENT KINASE 5 REGULATORY SUBUNIT 1 / TAU PROTEIN KINASE II / TPKII ...CDK5 ACTIVATOR 1 / CYCLIN-DEPENDENT KINASE 5 REGULATORY SUBUNIT 1 / TAU PROTEIN KINASE II / TPKII REGULATORY SUBUNIT / P23 / P25 / P35NCK5A


Mass: 23200.678 Da / Num. of mol.: 2 / Fragment: RESIDUES 100-307
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q15078
#3: Chemical ChemComp-ALH / 6-PHENYL[5H]PYRROLO[2,3-B]PYRAZINE / ALOISINE A


Mass: 267.326 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H17N3O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 294 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE ASP 144 ASN, CHAIN A AND B

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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: 2.8 Å3/Da / Density % sol: 56.4 %
Crystal growpH: 7
Details: 13% PEG 3350, 0.1M KI, 0.1M BISTRISPROPANE PH 7.0, 10MM DTT

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Data collection

DiffractionMean temperature: 287 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.933
DetectorType: ADSC CCD / Detector: CCD / Date: Sep 15, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.3→25 Å / Num. obs: 53731 / % possible obs: 95.4 % / Observed criterion σ(I): 2.5 / Redundancy: 6.2 % / Rmerge(I) obs: 0.104 / Net I/σ(I): 9.1
Reflection shellResolution: 2.3→2.4 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 2.6 / % possible all: 97.5

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1H4L

1h4l


Resolution: 2.3→19.76 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.921 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.293 / ESU R Free: 0.201 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.225 2713 5.1 %RANDOM
Rwork0.216 ---
obs0.216 50923 95.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 22.42 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å2-0.04 Å20 Å2
2---0.08 Å20 Å2
3---0.13 Å2
Refinement stepCycle: LAST / Resolution: 2.3→19.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6870 0 40 294 7204
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0217075
X-RAY DIFFRACTIONr_bond_other_d00.026476
X-RAY DIFFRACTIONr_angle_refined_deg1.8711.9799580
X-RAY DIFFRACTIONr_angle_other_deg3.697315092
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.225844
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.1210.21063
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.027696
X-RAY DIFFRACTIONr_gen_planes_other0.0090.021443
X-RAY DIFFRACTIONr_nbd_refined0.2360.21592
X-RAY DIFFRACTIONr_nbd_other0.3040.26873
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.1110.23414
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.210.2305
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.180.220
X-RAY DIFFRACTIONr_symmetry_vdw_other0.3530.2114
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2480.221
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8121.54269
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.47726908
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.62532806
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.9024.52672
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
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.219 211
Rwork0.227 3758
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)
12.6986-0.2144-1.24171.10040.00451.93650.0390.010.06960.0703-0.0747-0.078-0.04060.11230.03570.0393-0.0158-0.00350.0078-0.00570.0356-3.301755.83767.36
21.5356-0.26120.42134.0403-0.79642.93780.00310.174-0.0151-0.5765-0.0095-0.16240.17450.13590.00640.2684-0.0098-0.03210.0464-0.02430.121956.429115.171643.6887
34.5294-0.36570.67550.79410.45792.2072-0.0235-0.231-0.11680.11680.05860.07140.036-0.0799-0.03510.06210.038-0.00590.04340.01160.023622.901842.202717.4663
43.2944-0.6795-0.07241.4809-0.0530.59780.1324-0.0903-0.16660.1707-0.0921-0.50220.19160.5578-0.04030.73640.09720.1170.6714-0.06930.753287.34881.5342.0452
529.1874-20.91518.645615.1563-13.54212.2185-1.4619-0.90860.90131.1620.6903-0.7585-0.7676-0.58380.77160.2471-0.0002-0.00020.2478-0.00020.247232.72345.914217.661
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 24
2X-RAY DIFFRACTION1A25 - 38
3X-RAY DIFFRACTION1A39 - 82
4X-RAY DIFFRACTION1A83 - 291
5X-RAY DIFFRACTION2B2 - 21
6X-RAY DIFFRACTION2B29 - 38
7X-RAY DIFFRACTION2B43 - 82
8X-RAY DIFFRACTION2B83 - 291
9X-RAY DIFFRACTION3D145 - 293
10X-RAY DIFFRACTION4E147 - 166
11X-RAY DIFFRACTION4E167 - 293
12X-RAY DIFFRACTION5A1293
13X-RAY DIFFRACTION5B1288

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