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- PDB-6i5i: Crystal structure of CLK1 in complexed with furo[3,2-b]pyridine c... -

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Basic information

Entry
Database: PDB / ID: 6i5i
TitleCrystal structure of CLK1 in complexed with furo[3,2-b]pyridine compound 12h
ComponentsDual specificity protein kinase CLK1
KeywordsTRANSFERASE / splicing kinase / furopyridine / inhibitor / CLK / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


dual-specificity kinase / regulation of RNA splicing / protein serine/threonine/tyrosine kinase activity / non-membrane spanning protein tyrosine kinase activity / protein tyrosine kinase activity / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / nucleus
Similarity search - Function
: / 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. ...: / 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 / Alpha Beta
Similarity search - Domain/homology
Chem-H3E / Dual specificity protein kinase CLK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsChaikuad, A. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Paruch, K. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Angew. Chem. Int. Ed. Engl. / Year: 2019
Title: Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway.
Authors: Nemec, V. / Hylsova, M. / Maier, L. / Flegel, J. / Sievers, S. / Ziegler, S. / Schroder, M. / Berger, B.T. / Chaikuad, A. / Valcikova, B. / Uldrijan, S. / Drapela, S. / Soucek, K. / ...Authors: Nemec, V. / Hylsova, M. / Maier, L. / Flegel, J. / Sievers, S. / Ziegler, S. / Schroder, M. / Berger, B.T. / Chaikuad, A. / Valcikova, B. / Uldrijan, S. / Drapela, S. / Soucek, K. / Waldmann, H. / Knapp, S. / Paruch, K.
History
DepositionNov 13, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 9, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 23, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jan 24, 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

Downloads & links

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Assembly

Deposited unit
A: Dual specificity protein kinase CLK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,68214
Polymers39,5821
Non-polymers1,10013
Water6,648369
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2350 Å2
ΔGint36 kcal/mol
Surface area15350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.960, 64.010, 81.160
Angle α, β, γ (deg.)90.00, 122.71, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Dual specificity protein kinase CLK1 / CDC-like kinase 1


Mass: 39581.512 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CLK1, CLK / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3-pRARE2 / References: UniProt: P49759, dual-specificity kinase
#2: Chemical ChemComp-H3E / 5-(1-methylpyrazol-4-yl)-3-[1-(phenylmethyl)pyrazol-4-yl]furo[3,2-b]pyridine


Mass: 355.393 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17N5O
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 369 / 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: 2.54 Å3/Da / Density % sol: 51.55 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 9 / Details: 20% PEG 6000, 0.1M bicine pH 9.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.99 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99 Å / Relative weight: 1
ReflectionResolution: 1.6→49.32 Å / Num. obs: 51989 / % possible obs: 99.4 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.069 / Net I/σ(I): 8.5
Reflection shellResolution: 1.6→1.69 Å / Redundancy: 3 % / Rmerge(I) obs: 0.508 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 7542 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6G33

6g33


Resolution: 1.6→49.32 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.956 / SU B: 3.559 / SU ML: 0.061 / Cross valid method: THROUGHOUT / ESU R: 0.079 / ESU R Free: 0.081 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19557 2557 4.9 %RANDOM
Rwork0.16399 ---
obs0.16551 49432 99.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 23.596 Å2
Baniso -1Baniso -2Baniso -3
1-0.53 Å20 Å2-0.06 Å2
2---0.06 Å2-0 Å2
3----0.22 Å2
Refinement stepCycle: 1 / Resolution: 1.6→49.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2686 0 75 369 3130
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192877
X-RAY DIFFRACTIONr_bond_other_d0.0020.022725
X-RAY DIFFRACTIONr_angle_refined_deg1.6231.953883
X-RAY DIFFRACTIONr_angle_other_deg0.9436271
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9035349
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.07723.507134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.33715491
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.4271517
X-RAY DIFFRACTIONr_chiral_restr0.1080.2421
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023340
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02681
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
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_it1.1921.3831355
X-RAY DIFFRACTIONr_mcbond_other1.1911.3831355
X-RAY DIFFRACTIONr_mcangle_it2.0762.0631693
X-RAY DIFFRACTIONr_mcangle_other2.0752.0631694
X-RAY DIFFRACTIONr_scbond_it1.5021.4931522
X-RAY DIFFRACTIONr_scbond_other1.5021.4931522
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.4542.1542183
X-RAY DIFFRACTIONr_long_range_B_refined6.97812.4783614
X-RAY DIFFRACTIONr_long_range_B_other6.97812.4883615
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.6→1.642 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.319 178 -
Rwork0.27 3659 -
obs--99.51 %
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)
10.46650.1892-0.40550.6185-0.08180.52480.02540.0036-0.00960.0269-0.0341-0.0585-0.01620.01120.00870.0291-0.0119-0.03990.03230.00280.072420.45641.64610.792
20.3893-0.3745-0.49160.92940.1330.9953-0.16070.0552-0.01490.25170.02670.00470.1019-0.1040.1340.0954-0.0142-0.02320.0364-0.00560.07534.08635.12625.817
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-1 - 302
2X-RAY DIFFRACTION2A303 - 483

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