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- PDB-9epu: Crystal structure of the human CDKL5 kinase domain with compound ... -

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Basic information

Entry
Database: PDB / ID: 9epu
TitleCrystal structure of the human CDKL5 kinase domain with compound CAF-382
ComponentsCyclin-dependent kinase-like 5
KeywordsGENE REGULATION / Kinase
Function / homology
Function and homology information


regulation of dendrite development / regulation of cilium assembly / ciliary tip / positive regulation of dendrite morphogenesis / regulation of postsynapse organization / positive regulation of dendritic spine development / positive regulation of Rac protein signal transduction / dendritic growth cone / postsynaptic density, intracellular component / positive regulation of axon extension ...regulation of dendrite development / regulation of cilium assembly / ciliary tip / positive regulation of dendrite morphogenesis / regulation of postsynapse organization / positive regulation of dendritic spine development / positive regulation of Rac protein signal transduction / dendritic growth cone / postsynaptic density, intracellular component / positive regulation of axon extension / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / dendrite cytoplasm / ciliary basal body / neuron migration / modulation of chemical synaptic transmission / small GTPase binding / kinase activity / protein kinase activity / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / perinuclear region of cytoplasm / glutamatergic synapse / nucleoplasm / ATP binding / nucleus
Similarity search - Function
: / 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
Similarity search - Domain/homology
: / DI(HYDROXYETHYL)ETHER / Cyclin-dependent kinase-like 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsRichardson, W. / Chen, X. / Newman, J.A. / Bakshi, S. / Lakshminarayana, B. / Brooke, L. / Bullock, A.N.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Innovative Medicines Initiative875510 Switzerland
CitationJournal: To Be Published
Title: Crystal structure of the human CDKL5 kinase domain with compound CAF-382
Authors: Capener, J.L. / Kim, J.K. / Richardson, W. / Silvaroli, J.A. / Martinez, G.V. / Thorson, V.C. / Li, J. / Hoyt, K.R. / Satoskar, A.A. / Mallipattu, S.K. / Davidson, A.J. / Zepeda-Orozco, D. / ...Authors: Capener, J.L. / Kim, J.K. / Richardson, W. / Silvaroli, J.A. / Martinez, G.V. / Thorson, V.C. / Li, J. / Hoyt, K.R. / Satoskar, A.A. / Mallipattu, S.K. / Davidson, A.J. / Zepeda-Orozco, D. / Bajwa, A. / Bullock, A.N. / Axtman, A.D. / Pabla, N.S.
History
DepositionMar 20, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-dependent kinase-like 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9896
Polymers35,2321
Non-polymers7575
Water27015
1
A: Cyclin-dependent kinase-like 5
hetero molecules

A: Cyclin-dependent kinase-like 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,97712
Polymers70,4632
Non-polymers1,51410
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area2730 Å2
ΔGint-73 kcal/mol
Surface area24950 Å2
Unit cell
Length a, b, c (Å)89.077, 89.077, 132.647
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number182
Space group name H-MP6322
Space group name HallP6c2c
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/2
#3: y,-x+y,z+1/2
#4: -y,x-y,z
#5: -x+y,-x,z
#6: x-y,-y,-z
#7: -x,-x+y,-z
#8: -x,-y,z+1/2
#9: y,x,-z
#10: -y,-x,-z+1/2
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Cyclin-dependent kinase-like 5 / Serine/threonine-protein kinase 9


Mass: 35231.711 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDKL5, STK9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O76039, cyclin-dependent kinase

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Non-polymers , 5 types, 20 molecules

#2: Chemical ChemComp-A1H6P / ~{N}-[5-[(5-propan-2-yl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]piperidine-4-carboxamide


Mass: 366.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H22N4O2S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 15 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.37 Å3/Da / Density % sol: 48.07 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion
Details: 0.9 M lithium sulfate, 0.1 M tri-sodium citrate, and 0.7 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Dec 7, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.6→50.29 Å / Num. obs: 10172 / % possible obs: 100 % / Redundancy: 38.7 % / Biso Wilson estimate: 58.78 Å2 / CC1/2: 0.999 / Net I/σ(I): 11
Reflection shellResolution: 2.6→2.64 Å / Num. unique obs: 492 / CC1/2: 0.839

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→50.29 Å / SU ML: 0.367 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.2872
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.27 522 5.16 %
Rwork0.226 9595 -
obs0.2282 10117 99.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 65.89 Å2
Refinement stepCycle: LAST / Resolution: 2.6→50.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 47 15 2275
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01322305
X-RAY DIFFRACTIONf_angle_d1.80123112
X-RAY DIFFRACTIONf_chiral_restr0.102344
X-RAY DIFFRACTIONf_plane_restr0.0181394
X-RAY DIFFRACTIONf_dihedral_angle_d8.7415320
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.860.37721300.30262311X-RAY DIFFRACTION99.11
2.86-3.270.36241370.2932335X-RAY DIFFRACTION99.72
3.27-4.120.25771280.21482380X-RAY DIFFRACTION99.84
4.12-50.290.22171270.19942569X-RAY DIFFRACTION99.93
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)
14.710745919450.576015919964-1.581796083055.8762751083-2.226389409176.77015879775-0.2431910904640.2805441063620.03020435372280.615612895140.245127466463-0.3221512439710.7151061076220.4361546934690.1492609759520.5512806421180.1196368675310.005422924606060.4836320928020.03289499732430.3381975149726.535451755419.16414704028.02613155693
22.14601415343-0.247567853844-0.2789533498854.34418728161-2.039370731525.91191604942-0.322953850153-0.3460325171-0.1519351224060.4192840475230.307194145915-0.4291615929630.3251204487190.227590282267-0.0004449151165980.4302541849420.0509002754968-0.06298484825280.5119311979030.001796575726360.45577581785128.901411443220.7581287763-3.70605216337
34.221930347790.7131711343790.1318963502523.46611180731-0.4440238903765.45144948334-0.2092845886110.0181684447352-0.339022453383-0.2237238361650.2373116195890.1570982097720.631057301409-0.684377888573-0.05204072307970.356824366551-0.0389566366797-0.004434838238320.362985254637-0.02325507664490.309385424220.884472862721.9348616587-16.3707591607
44.211791666031.74159627079-0.4065526915854.67510630927-0.007422686079754.97607760279-0.317001740850.440447452502-0.342577729536-0.6734748181980.4701446294340.3728893656820.775590267251-1.04642629283-0.09083917368350.477624944765-0.141567159081-0.0903275425010.6020610519960.04437238825220.34145207576918.317157884125.0486696972-28.1765197245
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 12 through 56 )12 - 561 - 36
22chain 'A' and (resid 57 through 108 )57 - 10837 - 84
33chain 'A' and (resid 109 through 227 )109 - 22785 - 200
44chain 'A' and (resid 228 through 303 )228 - 303201 - 276

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