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- PDB-7vds: The structure of cyclin-dependent kinase 5 (CDK5) in complex with... -

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Basic information

Entry
Database: PDB / ID: 7vds
TitleThe structure of cyclin-dependent kinase 5 (CDK5) in complex with p25 and Compound 24
Components
  • Cyclin-dependent kinase 5 activator 1
  • Cyclin-dependent-like kinase 5, p25
KeywordsTRANSFERASE / CDK5 / p25
Function / homology
Function and homology information


superior olivary nucleus maturation / acetylcholine receptor activator activity / protein kinase 5 complex / G1 to G0 transition involved in cell differentiation / ErbB-2 class receptor binding / negative regulation of synaptic plasticity / regulation of cell cycle phase transition / contractile muscle fiber / Activated NTRK2 signals through CDK5 / positive regulation of calcium ion-dependent exocytosis ...superior olivary nucleus maturation / acetylcholine receptor activator activity / protein kinase 5 complex / G1 to G0 transition involved in cell differentiation / ErbB-2 class receptor binding / negative regulation of synaptic plasticity / regulation of cell cycle phase transition / contractile muscle fiber / Activated NTRK2 signals through CDK5 / positive regulation of calcium ion-dependent exocytosis / neuron cell-cell adhesion / layer formation in cerebral cortex / negative regulation of axon extension / corpus callosum development / receptor catabolic process / protein localization to synapse / cerebellar cortex formation / regulation of dendritic spine morphogenesis / CRMPs in Sema3A signaling / NGF-stimulated transcription / ErbB-3 class receptor binding / synaptic transmission, dopaminergic / negative regulation of protein export from nucleus / motor neuron axon guidance / cyclin-dependent protein serine/threonine kinase activator activity / axon extension / axonal fasciculation / calcium ion import / regulation of synaptic vesicle cycle / regulation of synaptic vesicle recycling / embryo development ending in birth or egg hatching / regulation of cyclin-dependent protein serine/threonine kinase activity / regulation of neuron differentiation / dendrite morphogenesis / tau-protein kinase activity / phosphorylation / synaptic vesicle transport / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / receptor clustering / beta-tubulin binding / central nervous system neuron development / oligodendrocyte differentiation / behavioral response to cocaine / synaptic vesicle exocytosis / negative regulation of cell cycle / synaptic vesicle endocytosis / protein kinase activator activity / DARPP-32 events / positive regulation of protein targeting to membrane / ephrin receptor signaling pathway / alpha-tubulin binding / regulation of macroautophagy / cyclin-dependent protein serine/threonine kinase activity / Schwann cell development / regulation of protein localization to plasma membrane / skeletal muscle tissue development / regulation of synaptic transmission, glutamatergic / synapse assembly / cyclin-dependent protein kinase holoenzyme complex / negative regulation of proteolysis / ionotropic glutamate receptor binding / ephrin receptor binding / sensory perception of pain / NPAS4 regulates expression of target genes / positive regulation of microtubule polymerization / negative regulation of protein ubiquitination / peptidyl-threonine phosphorylation / ionotropic glutamate receptor signaling pathway / cerebellum development / axonogenesis / axon guidance / regulation of cell migration / protein serine/threonine kinase activator activity / hippocampus development / cell-matrix adhesion / excitatory postsynaptic potential / synaptic transmission, glutamatergic / filopodium / regulation of actin cytoskeleton organization / intracellular protein transport / Hsp90 protein binding / brain development / neuromuscular junction / visual learning / regulation of synaptic plasticity / tau protein binding / microtubule cytoskeleton organization / G protein-coupled acetylcholine receptor signaling pathway / neuron differentiation / cellular response to amyloid-beta / neuron migration / neuron projection development / actin filament binding / kinase activity / p53 binding / rhythmic process / positive regulation of neuron apoptotic process / cell junction / lamellipodium / presynapse
Similarity search - Function
Cyclin-dependent kinase 5 activator protein / Cyclin-dependent kinase 5 activator / 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. ...Cyclin-dependent kinase 5 activator protein / Cyclin-dependent kinase 5 activator / 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
Chem-61U / Cyclin-dependent kinase 5 / Cyclin-dependent kinase 5 activator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.05 Å
AuthorsMalojcic, G. / Clugston, S.L. / Daniels, M. / Harmange, J.C. / Ledeborer, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery and Optimization of Highly Selective Inhibitors of CDK5.
Authors: Daniels, M.H. / Malojcic, G. / Clugston, S.L. / Williams, B. / Coeffet-Le Gal, M. / Pan-Zhou, X.R. / Venkatachalan, S. / Harmange, J.C. / Ledeboer, M.
History
DepositionSep 7, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-dependent-like kinase 5, p25
B: Cyclin-dependent-like kinase 5, p25
C: Cyclin-dependent kinase 5 activator 1
D: Cyclin-dependent kinase 5 activator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,41952
Polymers113,2764
Non-polymers3,14248
Water1,24369
1
A: Cyclin-dependent-like kinase 5, p25
C: Cyclin-dependent kinase 5 activator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,59447
Polymers56,6382
Non-polymers2,95645
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8610 Å2
ΔGint-140 kcal/mol
Surface area20600 Å2
MethodPISA
2
B: Cyclin-dependent-like kinase 5, p25
D: Cyclin-dependent kinase 5 activator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,8245
Polymers56,6382
Non-polymers1863
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3150 Å2
ΔGint-13 kcal/mol
Surface area20110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.060, 118.060, 153.690
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12C
22D

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLYGLYSERSERAA11 - 28711 - 287
21TYRTYRSERSERBB4 - 2874 - 287
12SERSERGLUGLUCC147 - 29249 - 194
22SERSERGLUGLUDD147 - 29249 - 194

NCS ensembles :
ID
1
2

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Components

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Protein , 2 types, 4 molecules ABCD

#1: Protein Cyclin-dependent-like kinase 5, p25 / Cell division protein kinase 5


Mass: 33306.344 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK5, CDKN5 / Plasmid: pFastBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q00535, non-specific serine/threonine protein kinase
#2: Protein Cyclin-dependent kinase 5 activator 1


Mass: 23331.875 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK5R1, CDK5R, NCK5A / Plasmid: pFastBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q15078

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Non-polymers , 5 types, 117 molecules

#3: Chemical ChemComp-61U / 5-fluoranyl-4-[[2-[(1R)-1-(1-methylpiperidin-4-yl)-1-oxidanyl-ethyl]-1,6-naphthyridin-7-yl]amino]-2-morpholin-4-yl-benzenecarbonitrile


Mass: 490.572 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H31FN6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 19 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.73 Å3/Da / Density % sol: 54.94 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1M MES pH 5.5, 0.3M MgCl2, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.12713 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Feb 29, 2020
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.12713 Å / Relative weight: 1
ReflectionResolution: 3.05→48.51 Å / Num. obs: 24161 / % possible obs: 100 % / Redundancy: 18.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.144 / Rpim(I) all: 0.035 / Rrim(I) all: 0.149 / Net I/σ(I): 14.3 / Num. measured all: 437075 / Scaling rejects: 4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.05-3.2618.62.5658002943080.5650.6052.6361.4100
8.63-48.5116.70.0541966811770.9990.0130.05544.799.4

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3O0G

3o0g


Resolution: 3.05→48.51 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.923 / SU B: 23.569 / SU ML: 0.408 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.473 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2715 1207 5 %RANDOM
Rwork0.2254 ---
obs0.2279 22918 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 373.64 Å2 / Biso mean: 133.419 Å2 / Biso min: 54.52 Å2
Baniso -1Baniso -2Baniso -3
1--0.14 Å2-0.07 Å2-0 Å2
2---0.14 Å20 Å2
3---0.44 Å2
Refinement stepCycle: final / Resolution: 3.05→48.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6954 0 183 69 7206
Biso mean--125.04 86.75 -
Num. residues----863
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0137268
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176994
X-RAY DIFFRACTIONr_angle_refined_deg1.2441.6539795
X-RAY DIFFRACTIONr_angle_other_deg1.0481.58616125
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0435860
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.24621.936377
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.435151263
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.621549
X-RAY DIFFRACTIONr_chiral_restr0.0470.2890
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.027979
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021654
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A82750.13
12B82750.13
21C43950.14
22D43950.14
LS refinement shellResolution: 3.05→3.129 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.394 81 -
Rwork0.36 1692 -
all-1773 -
obs--99.77 %

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