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- PDB-8v42: Structure of Human Vaccinia-related Kinase 1 (VRK1) Bound to ACH000400 -

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Basic information

Entry
Database: PDB / ID: 8v42
TitleStructure of Human Vaccinia-related Kinase 1 (VRK1) Bound to ACH000400
ComponentsSerine/threonine-protein kinase VRK1
KeywordsTRANSFERASE / protein kinase / inhibitor / co-crystal
Function / homology
Function and homology information


histone H2AX kinase activity / Golgi disassembly / Cajal body organization / histone H3T3 kinase activity / Nuclear Envelope Breakdown / positive regulation of protein localization to chromatin / mitotic nuclear membrane disassembly / histone H3S10 kinase activity / regulation of neuron migration / Initiation of Nuclear Envelope (NE) Reformation ...histone H2AX kinase activity / Golgi disassembly / Cajal body organization / histone H3T3 kinase activity / Nuclear Envelope Breakdown / positive regulation of protein localization to chromatin / mitotic nuclear membrane disassembly / histone H3S10 kinase activity / regulation of neuron migration / Initiation of Nuclear Envelope (NE) Reformation / Golgi stack / nucleosomal DNA binding / Cajal body / neuron projection development / kinase activity / protein autophosphorylation / histone binding / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / chromatin remodeling / cell division / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response / protein kinase binding / chromatin / nucleolus / signal transduction / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
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 / : / Serine/threonine-protein kinase VRK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsCounago, R.M. / de Souza, G.P. / Azevedo, A. / Guimaraes, C. / Mascarello, A. / Gama, F. / Ferreira, M. / Arruda, P.
Funding support Brazil, 1items
OrganizationGrant numberCountry
Sao Paulo Research Foundation (FAPESP) Brazil
CitationJournal: J.Med.Chem. / Year: 2024
Title: Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1 delta / epsilon.
Authors: de Souza Gama, F.H. / Dutra, L.A. / Hawgood, M. / Dos Reis, C.V. / Serafim, R.A.M. / Ferreira Jr., M.A. / Teodoro, B.V.M. / Takarada, J.E. / Santiago, A.S. / Balourdas, D.I. / Nilsson, A.S. ...Authors: de Souza Gama, F.H. / Dutra, L.A. / Hawgood, M. / Dos Reis, C.V. / Serafim, R.A.M. / Ferreira Jr., M.A. / Teodoro, B.V.M. / Takarada, J.E. / Santiago, A.S. / Balourdas, D.I. / Nilsson, A.S. / Urien, B. / Almeida, V.M. / Gileadi, C. / Ramos, P.Z. / Salmazo, A. / Vasconcelos, S.N.S. / Cunha, M.R. / Mueller, S. / Knapp, S. / Massirer, K.B. / Elkins, J.M. / Gileadi, O. / Mascarello, A. / Lemmens, B.B.L.G. / Guimaraes, C.R.W. / Azevedo, H. / Counago, R.M.
History
DepositionNov 28, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase VRK1
B: Serine/threonine-protein kinase VRK1
C: Serine/threonine-protein kinase VRK1
D: Serine/threonine-protein kinase VRK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,89611
Polymers164,5534
Non-polymers1,3437
Water2,558142
1
A: Serine/threonine-protein kinase VRK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2442
Polymers41,1381
Non-polymers1061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase VRK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,5652
Polymers41,1381
Non-polymers4261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Serine/threonine-protein kinase VRK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,3303
Polymers41,1381
Non-polymers1922
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Serine/threonine-protein kinase VRK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,7574
Polymers41,1381
Non-polymers6193
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.552, 96.615, 190.858
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Serine/threonine-protein kinase VRK1 / Vaccinia-related kinase 1


Mass: 41138.125 Da / Num. of mol.: 4
Mutation: K34A,K35A,E36A,E212A,K214A,E215A,E292A,K293A,K295A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VRK1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q99986, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#3: Chemical ChemComp-YD9 / (7S)-2-(3,5-difluoro-4-hydroxyanilino)-7-methyl-5-[(1,2-oxazol-5-yl)methyl]-8-(prop-2-yn-1-yl)-7,8-dihydropteridin-6(5H)-one


Mass: 426.376 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H16F2N6O3
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 142 / Source method: isolated from a natural source / Formula: H2O
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: 2.56 Å3/Da / Density % sol: 52.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 22% PEG3350, 20 mM Li2SO4, 0.1 M Buffer system SBG pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9686 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 8, 2021
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 2.3→19.93 Å / Num. obs: 75682 / % possible obs: 99.7 % / Redundancy: 13.6 % / Rmerge(I) obs: 0.176 / Net I/σ(I): 11.8
Reflection shellResolution: 2.3→2.35 Å / Redundancy: 13.8 % / Rmerge(I) obs: 2.417 / Mean I/σ(I) obs: 1.8 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→19.93 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.944 / SU B: 14.927 / SU ML: 0.166 / Cross valid method: THROUGHOUT / ESU R: 0.259 / ESU R Free: 0.201
Details: HYDROGENS HAVE BEEN ADDED IN THEIR RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.231 3800 5.027 %RANDOM
Rwork0.199 ---
obs-75597 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 53.97 Å2
Baniso -1Baniso -2Baniso -3
1-1.304 Å20 Å20 Å2
2--0.523 Å20 Å2
3----1.827 Å2
Refinement stepCycle: LAST / Resolution: 2.3→19.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9661 0 89 142 9892
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0129993
X-RAY DIFFRACTIONr_bond_other_d0.0010.0169257
X-RAY DIFFRACTIONr_angle_refined_deg0.9161.83513555
X-RAY DIFFRACTIONr_angle_other_deg0.3611.76821248
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.64151218
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.3145.85770
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.942101615
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0470.21459
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0211780
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022300
X-RAY DIFFRACTIONr_nbd_refined0.190.21965
X-RAY DIFFRACTIONr_nbd_other0.1570.2102
X-RAY DIFFRACTIONr_nbtor_refined0.1780.24868
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1160.2233
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4994.4044905
X-RAY DIFFRACTIONr_mcbond_other1.4994.4044905
X-RAY DIFFRACTIONr_mcangle_it2.5377.9046106
X-RAY DIFFRACTIONr_mcangle_other2.5377.9056107
X-RAY DIFFRACTIONr_scbond_it1.7734.5025088
X-RAY DIFFRACTIONr_scbond_other1.7734.5025088
X-RAY DIFFRACTIONr_scangle_it3.0358.2397447
X-RAY DIFFRACTIONr_scangle_other3.0358.247448
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% reflection
Rfree0.304 286 -
Rwork0.283 5121 -
obs--99.54 %
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)
10.182-0.2626-0.43520.47830.63521.23850.0607-0.00080.0212-0.05590.0022-0.0495-0.1652-0.0343-0.06290.1730.00850.03750.2156-0.01590.017118.91071.844520.5107
20.38010.1195-0.33060.6475-0.16310.9345-0.0560.08790.0262-0.03880.0390.11060.0229-0.1610.0170.1166-0.0242-0.00920.1955-0.00990.0236-15.47931.678451.9377
30.1759-0.17190.34060.3026-0.39521.2978-0.01570.00860.00130.01570.0658-0.00310.101-0.2024-0.05010.1027-0.0502-0.02110.2520.03680.0086-25.1071-45.227127.3469
40.3358-0.0843-0.1660.7737-0.591.4516-0.0150.03770.06820.14980.0741-0.0758-0.167-0.0979-0.05910.06990.0385-0.00060.20830.00770.0288-25.0188-9.908-3.0314

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