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- PDB-4au8: Crystal structure of compound 4a in complex with cdk5, showing an... -

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Basic information

Entry
Database: PDB / ID: 4au8
TitleCrystal structure of compound 4a in complex with cdk5, showing an unusual binding mode to the hinge region via a water molecule
ComponentsCYCLIN-DEPENDENT KINASE 5
KeywordsTRANSFERASE / CDK2 / ALZHEIMER DISEASE
Function / homology
Function and homology information


protein kinase 5 complex / acetylcholine receptor activator activity / ErbB-2 class receptor binding / negative regulation of synaptic plasticity / Activated NTRK2 signals through CDK5 / positive regulation of calcium ion-dependent exocytosis / layer formation in cerebral cortex / negative regulation of axon extension / protein localization to synapse / receptor catabolic process ...protein kinase 5 complex / acetylcholine receptor activator activity / ErbB-2 class receptor binding / negative regulation of synaptic plasticity / Activated NTRK2 signals through CDK5 / positive regulation of calcium ion-dependent exocytosis / layer formation in cerebral cortex / negative regulation of axon extension / 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 / axon extension / calcium ion import / regulation of synaptic vesicle recycling / negative regulation of protein export from nucleus / motor neuron axon guidance / dendrite morphogenesis / synaptic vesicle transport / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / tau-protein kinase activity / receptor clustering / central nervous system neuron development / oligodendrocyte differentiation / synaptic vesicle exocytosis / behavioral response to cocaine / 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 / 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 / sensory perception of pain / negative regulation of protein ubiquitination / regulation of synaptic transmission, glutamatergic / synapse assembly / excitatory postsynaptic potential / NPAS4 regulates expression of target genes / axonogenesis / cell-matrix adhesion / filopodium / synaptic transmission, glutamatergic / hippocampus development / negative regulation of proteolysis / intracellular protein transport / Hsp90 protein binding / peptidyl-threonine phosphorylation / neuron migration / regulation of synaptic plasticity / tau protein binding / neuromuscular junction / visual learning / neuron differentiation / microtubule cytoskeleton organization / neuron projection development / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / rhythmic process / p53 binding / presynapse / lamellipodium / cell junction / Factors involved in megakaryocyte development and platelet production / kinase activity / growth cone / perikaryon / chemical synaptic transmission / peptidyl-serine phosphorylation / neuron apoptotic process / regulation of apoptotic process / Regulation of TP53 Activity through Phosphorylation / postsynaptic density / regulation of cell cycle / non-specific serine/threonine protein kinase / neuron projection / protein kinase activity / cell cycle / cell division / axon / phosphorylation / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / negative regulation of DNA-templated transcription / dendrite / neuronal cell body / nucleoplasm / ATP binding / membrane / nucleus
Similarity search - Function
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. ...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
IMIDAZOLE / 4-(1,3-benzothiazol-2-yl)thiophene-2-sulfonamide / Cyclin-dependent kinase 5
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsMalmstrom, J. / Viklund, J. / Slivo, C. / Costa, A. / Maudet, M. / Sandelin, C. / Hiller, G. / Olsson, L.L. / Aagaard, A. / Geschwindner, S. ...Malmstrom, J. / Viklund, J. / Slivo, C. / Costa, A. / Maudet, M. / Sandelin, C. / Hiller, G. / Olsson, L.L. / Aagaard, A. / Geschwindner, S. / Xue, Y. / Vasange, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Synthesis and Structure-Activity Relationship of 4-(1,3-Benzothiazol-2-Yl)-Thiophene-2-Sulfonamides as Cyclin-Dependent Kinase 5 (Cdk5)/P25 Inhibitors.
Authors: Malmstrom, J. / Viklund, J. / Slivo, C. / Costa, A. / Maudet, M. / Sandelin, C. / Hiller, G. / Olsson, L.L. / Aagaard, A. / Geschwindner, S. / Xue, Y. / Vasange, M.
History
DepositionMay 14, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 27, 2013Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CYCLIN-DEPENDENT KINASE 5
B: CYCLIN-DEPENDENT KINASE 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,48411
Polymers67,2452
Non-polymers1,2389
Water8,539474
1
A: CYCLIN-DEPENDENT KINASE 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2075
Polymers33,6231
Non-polymers5854
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CYCLIN-DEPENDENT KINASE 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2766
Polymers33,6231
Non-polymers6545
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2710 Å2
ΔGint-95.9 kcal/mol
Surface area25480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.271, 83.271, 191.766
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-2105-

HOH

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Components

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


Mass: 33622.719 Da / Num. of mol.: 2 / Fragment: RESIDUES 2-292
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBACHTB / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q00535, cyclin-dependent kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-Z3R / 4-(1,3-benzothiazol-2-yl)thiophene-2-sulfonamide


Mass: 296.388 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H8N2O2S3
#4: Chemical ChemComp-IMD / IMIDAZOLE / Imidazole


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 474 / Source method: isolated from a natural source / Formula: H2O

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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: 2.5 Å3/Da / Density % sol: 51 % / Description: NONE
Crystal growpH: 5.4 / Details: pH 5.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.94
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 11, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.94 Å / Relative weight: 1
ReflectionResolution: 1.9→47.95 Å / Num. obs: 53688 / % possible obs: 99.4 % / Observed criterion σ(I): 0 / Redundancy: 5.1 % / Biso Wilson estimate: 27.23 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 16.5
Reflection shellResolution: 1.9→1.95 Å / Redundancy: 4 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 3.1 / % possible all: 98.9

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Processing

Software
NameVersionClassification
BUSTER2.11.1refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: UNPUBLISHED CDK5 COMPLEX

Resolution: 1.9→47.94 Å / Cor.coef. Fo:Fc: 0.9383 / Cor.coef. Fo:Fc free: 0.9189 / SU R Cruickshank DPI: 0.143 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.153 / SU Rfree Blow DPI: 0.141 / SU Rfree Cruickshank DPI: 0.136
RfactorNum. reflection% reflectionSelection details
Rfree0.2343 2726 5.09 %RANDOM
Rwork0.1955 ---
obs0.1974 53604 99.22 %-
Displacement parametersBiso mean: 33.17 Å2
Baniso -1Baniso -2Baniso -3
1--4.0169 Å20 Å20 Å2
2---4.0169 Å20 Å2
3---8.0338 Å2
Refine analyzeLuzzati coordinate error obs: 0.219 Å
Refinement stepCycle: LAST / Resolution: 1.9→47.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4443 0 71 474 4988
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014619HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.026250HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1602SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes108HARMONIC2
X-RAY DIFFRACTIONt_gen_planes652HARMONIC5
X-RAY DIFFRACTIONt_it4619HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.12
X-RAY DIFFRACTIONt_other_torsion18.42
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion567SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5591SEMIHARMONIC4
LS refinement shellResolution: 1.9→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3534 187 4.87 %
Rwork0.2826 3654 -
all0.2859 3841 -
obs--99.22 %

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