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- PDB-7ncf: Crystal structure of HIPK2 in complex with MU135 (compound 21e) -

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Basic information

Entry
Database: PDB / ID: 7ncf
TitleCrystal structure of HIPK2 in complex with MU135 (compound 21e)
ComponentsHomeodomain-interacting protein kinase 2
KeywordsTRANSFERASE / kinase / HIPK2 / kinase inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


lens induction in camera-type eye / iris morphogenesis / embryonic retina morphogenesis in camera-type eye / embryonic camera-type eye morphogenesis / retina layer formation / Physiological factors / PML body organization / voluntary musculoskeletal movement / eye development / YAP1- and WWTR1 (TAZ)-stimulated gene expression ...lens induction in camera-type eye / iris morphogenesis / embryonic retina morphogenesis in camera-type eye / embryonic camera-type eye morphogenesis / retina layer formation / Physiological factors / PML body organization / voluntary musculoskeletal movement / eye development / YAP1- and WWTR1 (TAZ)-stimulated gene expression / SMAD protein signal transduction / adult walking behavior / virion binding / anterior/posterior pattern specification / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / smoothened signaling pathway / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / positive regulation of transforming growth factor beta receptor signaling pathway / SMAD binding / Regulation of MECP2 expression and activity / negative regulation of BMP signaling pathway / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of DNA binding / negative regulation of ubiquitin-dependent protein catabolic process / intrinsic apoptotic signaling pathway / erythrocyte differentiation / transforming growth factor beta receptor signaling pathway / SUMOylation of transcription cofactors / regulation of signal transduction by p53 class mediator / positive regulation of JNK cascade / peptidyl-threonine phosphorylation / neuron differentiation / PML body / positive regulation of DNA-binding transcription factor activity / cytoplasmic stress granule / RNA polymerase II transcription regulator complex / positive regulation of angiogenesis / transcription corepressor activity / positive regulation of protein binding / cellular response to hypoxia / peptidyl-serine phosphorylation / protein tyrosine kinase activity / neuron apoptotic process / Regulation of TP53 Activity through Phosphorylation / RNA polymerase II-specific DNA-binding transcription factor binding / negative regulation of neuron apoptotic process / cell population proliferation / transcription coactivator activity / nuclear body / non-specific serine/threonine protein kinase / regulation of cell cycle / protein kinase activity / positive regulation of protein phosphorylation / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus / cytoplasm
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
Chem-U82 / Homeodomain-interacting protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.72 Å
AuthorsChaikuad, A. / Paruch, K. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Eur.J.Med.Chem. / Year: 2021
Title: Highly selective inhibitors of protein kinases CLK and HIPK with the furo[3,2-b]pyridine core.
Authors: Nemec, V. / Maier, L. / Berger, B.T. / Chaikuad, A. / Drapela, S. / Soucek, K. / Knapp, S. / Paruch, K.
History
DepositionJan 28, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 3, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Homeodomain-interacting protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7642
Polymers42,4471
Non-polymers3171
Water41423
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area17140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)133.855, 133.855, 56.771
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number171
Space group name H-MP62

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Components

#1: Protein Homeodomain-interacting protein kinase 2 / hHIPk2


Mass: 42446.516 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HIPK2 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2
References: UniProt: Q9H2X6, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-U82 / 3-(4-Tert-butylphenyl)-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine / 3-(4-~{tert}-butylphenyl)-5-(1~{H}-pyrazol-4-yl)furo[3,2-b]pyridine


Mass: 317.384 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 3.46 Å3/Da / Density % sol: 64.44 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 10% v/v isopropanol, 0.2 M NaCl and 0.1 M HEPES, pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Dec 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.72→43.81 Å / Num. obs: 15846 / % possible obs: 99.9 % / Redundancy: 8.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.073 / Rpim(I) all: 0.028 / Rrim(I) all: 0.082 / Net I/σ(I): 17.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.72-2.879.10.992223030.7750.3721.123100
8.6-43.8180.0285370.9990.010.0399

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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: 6p5s

6p5s


Resolution: 2.72→43.81 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.919 / SU B: 24.449 / SU ML: 0.231 / SU R Cruickshank DPI: 0.5011 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.501 / ESU R Free: 0.306 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2514 741 4.7 %RANDOM
Rwork0.1948 ---
obs0.1973 15089 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 192.85 Å2 / Biso mean: 89.316 Å2 / Biso min: 54.43 Å2
Baniso -1Baniso -2Baniso -3
1-1.36 Å20.68 Å20 Å2
2--1.36 Å2-0 Å2
3----4.43 Å2
Refinement stepCycle: final / Resolution: 2.72→43.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2880 0 24 23 2927
Biso mean--76.72 73.47 -
Num. residues----355
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0132973
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172813
X-RAY DIFFRACTIONr_angle_refined_deg1.2491.664034
X-RAY DIFFRACTIONr_angle_other_deg1.171.5876483
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9825354
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.97322.353153
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.1715524
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7161518
X-RAY DIFFRACTIONr_chiral_restr0.0710.2384
X-RAY DIFFRACTIONr_gen_planes_refined0.010.023296
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02683
LS refinement shellResolution: 2.72→2.79 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.389 54 -
Rwork0.302 1109 -
all-1163 -
obs--99.66 %
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)
13.8093-1.2612-0.57938.437-1.10722.0157-0.0615-0.2020.37730.94140.17770.461-0.3093-0.3038-0.11620.4243-0.03620.11670.19420.010.4846-40.898-44.25910.68
21.7383-0.9816-0.04394.3211-0.61151.9310.02240.0638-0.1157-0.1864-0.02810.0620.09390.23710.00570.01450.021-0.01650.0707-0.05080.0674-29.354-27.067-7.537
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A181 - 254
2X-RAY DIFFRACTION2A255 - 535

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