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

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Basic information

Entry
Database: PDB / ID: 1unh
TitleStructural mechanism for the inhibition of CDK5-p25 by roscovitine, aloisine and indirubin.
Components
  • CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1
  • CYCLIN-DEPENDENT KINASE 5
KeywordsCELL CYCLE / NEURODEGENERATIVE DISEASES / INDIRUBIN
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 / regulation of synaptic vesicle cycle / protein localization to synapse / 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 / calcium ion import / axon extension / 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 / cell-matrix adhesion / axonogenesis / filopodium / synaptic transmission, glutamatergic / axon guidance / hippocampus development / regulation of actin cytoskeleton organization / negative regulation of proteolysis / intracellular protein transport / brain development / Hsp90 protein binding / neuron migration / regulation of synaptic plasticity / peptidyl-threonine phosphorylation / tau protein binding / neuromuscular junction / visual learning / G protein-coupled acetylcholine receptor signaling pathway / microtubule cytoskeleton organization / neuron differentiation / cellular response to amyloid-beta / neuron projection development / 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
Chem-IXM / Cyclin-dependent kinase 5 / Cyclin-dependent kinase 5 activator 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 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: CYCLIN-DEPENDENT KINASE 5
B: CYCLIN-DEPENDENT 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)113,6556
Polymers113,1004
Non-polymers5552
Water3,783210
1
A: CYCLIN-DEPENDENT KINASE 5
D: CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,8273
Polymers56,5502
Non-polymers2771
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3460 Å2
ΔGint-15.4 kcal/mol
Surface area19180 Å2
MethodPISA
2
B: CYCLIN-DEPENDENT KINASE 5
E: CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,8273
Polymers56,5502
Non-polymers2771
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3410 Å2
ΔGint-15.2 kcal/mol
Surface area19170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)149.541, 90.124, 83.158
Angle α, β, γ (deg.)90.00, 93.29, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein CYCLIN-DEPENDENT 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-IXM / (Z)-1H,1'H-[2,3']BIINDOLYLIDENE-3,2'-DIONE-3-OXIME / INDIRUBIN-3'-MONOXIME


Mass: 277.277 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H11N3O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 210 / 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: 2.6 Å3/Da / Density % sol: 51.25 %
Crystal growpH: 7
Details: 13% PEG 3350, 0.1 M KI 0.1 M BISTRISPROPANE PH 7.0, 10 MM DTT

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Data collection

DiffractionMean temperature: 287 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.933
DetectorType: ADSC CCD / Detector: CCD / Date: Apr 15, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.25→30 Å / Num. obs: 50596 / % possible obs: 98.8 % / Observed criterion σ(I): 2.5 / Redundancy: 17.2 % / Rmerge(I) obs: 0.075 / Net I/σ(I): 20.4
Reflection shellResolution: 2.25→2.3 Å / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 4.5 / % possible all: 99.9

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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: 2.35→19.88 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.936 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.377 / ESU R Free: 0.223 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23 2303 5 %RANDOM
Rwork0.229 ---
obs0.229 43327 99.3 %-
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: 38.5 Å2
Baniso -1Baniso -2Baniso -3
1-0.08 Å20 Å20.02 Å2
2---0.28 Å20 Å2
3---0.2 Å2
Refinement stepCycle: LAST / Resolution: 2.35→19.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6834 0 42 210 7086
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0217040
X-RAY DIFFRACTIONr_bond_other_d00.026442
X-RAY DIFFRACTIONr_angle_refined_deg2.0461.989530
X-RAY DIFFRACTIONr_angle_other_deg3.711315004
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2195836
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_restr0.0960.21056
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.027658
X-RAY DIFFRACTIONr_gen_planes_other0.0070.021456
X-RAY DIFFRACTIONr_nbd_refined0.2870.21700
X-RAY DIFFRACTIONr_nbd_other0.3090.26670
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.1110.23311
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2870.2264
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1730.212
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2730.231
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1730.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6821.54234
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.28626846
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.15432806
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.2884.52684
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: 2.35→2.41 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.282 172
Rwork0.267 3177
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)
12.79160.2156-0.68742.25960.23052.97030.0218-0.06010.14630.04450.0515-0.0469-0.05580.0144-0.07330.0797-0.0072-0.06070.07010.01530.047645.69954.573326.3756
22.7816-0.27910.662.0697-0.00052.87940.0266-0.013-0.1145-0.1420.0292-0.09690.03890.0115-0.05580.0983-0.0190.07330.07630.00280.118646.18533.598116.2967
34.03610.35520.6483.52650.86683.405-0.06920.4298-0.2504-0.1101-0.00810.55240.0837-0.36890.07730.0987-0.0395-0.0010.2180.00480.251217.0763-8.909325.4588
44.57-0.9245-0.6583.8340.55133.0059-0.1396-0.49820.12680.15420.08880.3859-0.0153-0.19820.05080.1580.017-0.03290.1540.01450.140217.474846.725413.5262
5-2.0671-3.19467.10284.8136-2.5237-7.1878-0.59950.14650.2826-0.2662-0.7603-0.5134-0.17580.52431.35980.2793-0.00230.01090.2882-0.02660.29139.854818.839320.8793
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 24
2X-RAY DIFFRACTION1A25 - 38
3X-RAY DIFFRACTION1A39 - 82
4X-RAY DIFFRACTION1A83 - 287
5X-RAY DIFFRACTION2B2 - 24
6X-RAY DIFFRACTION2B25 - 38
7X-RAY DIFFRACTION2B39 - 82
8X-RAY DIFFRACTION2B83 - 287
9X-RAY DIFFRACTION3D147 - 293
10X-RAY DIFFRACTION4E147 - 293
11X-RAY DIFFRACTION5A1288
12X-RAY DIFFRACTION5B1288

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