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- PDB-9ez3: Crystal structure of human CLK3 bound to RN129 -

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Basic information

Entry
Database: PDB / ID: 9ez3
TitleCrystal structure of human CLK3 bound to RN129
ComponentsDual specificity protein kinase CLK3
KeywordsTRANSFERASE / CLK3 / Kinase / Inhibitor / TYPII
Function / homology
Function and homology information


dual-specificity kinase / intermediate filament cytoskeleton / regulation of RNA splicing / protein serine/threonine/tyrosine kinase activity / acrosomal vesicle / protein tyrosine kinase activity / protein phosphorylation / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity ...dual-specificity kinase / intermediate filament cytoskeleton / regulation of RNA splicing / protein serine/threonine/tyrosine kinase activity / acrosomal vesicle / protein tyrosine kinase activity / protein phosphorylation / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / RNA binding / nucleoplasm / ATP binding / identical protein binding / nucleus / membrane
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
: / Dual specificity protein kinase CLK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsKraemer, A. / Raig, N. / Knapp, S.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Innovative Medicines Initiative875510 Switzerland
CitationJournal: Sci Adv / Year: 2025
Title: Type II kinase inhibitors that target Parkinson's disease-associated LRRK2.
Authors: Nicolai D Raig / Katherine J Surridge / Marta Sanz-Murillo / Verena Dederer / Andreas Krämer / Martin P Schwalm / Nicholas M Lattal / Lewis Elson / Deep Chatterjee / Sebastian Mathea / ...Authors: Nicolai D Raig / Katherine J Surridge / Marta Sanz-Murillo / Verena Dederer / Andreas Krämer / Martin P Schwalm / Nicholas M Lattal / Lewis Elson / Deep Chatterjee / Sebastian Mathea / Thomas Hanke / Andres E Leschziner / Samara L Reck-Peterson / Stefan Knapp /
Abstract: Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson's disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have ...Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson's disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have entered clinical trials. Here, to our knowledge, we present the first type II kinase inhibitors that target LRRK2. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type I inhibitors. We designed these inhibitors with a combinatorial chemistry approach fusing selective LRRK2 type I and promiscuous type II inhibitors using iterative cycles of synthesis supported by structural biology and activity testing. Our lead compounds are selective and potent toward both LRRK2 and LRRK1, a close relative of LRRK2. Through cellular assays, cryo-electron microscopy structural analysis, and in vitro motility assays, we show that our inhibitors stabilize the open, inactive LRRK2 kinase conformation. These new conformation-specific compounds will be invaluable as tools to study LRRK2's function and regulation and expand the potential therapeutic options for PD.
History
DepositionApr 10, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 11, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 24, 2025Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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 / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dual specificity protein kinase CLK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0984
Polymers42,3181
Non-polymers7803
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area350 Å2
ΔGint-26 kcal/mol
Surface area16020 Å2
Unit cell
Length a, b, c (Å)74.587, 74.587, 97.035
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

#1: Protein Dual specificity protein kinase CLK3 / CDC-like kinase 3


Mass: 42318.414 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CLK3 / Production host: Escherichia coli (E. coli) / References: UniProt: P49761, dual-specificity kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-A1H74 / 1-(5-~{tert}-butyl-2-quinolin-6-yl-pyrazol-3-yl)-3-[3-(4-morpholin-4-yl-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]urea


Mass: 587.674 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H33N9O2 / Feature type: SUBJECT OF INVESTIGATION
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: 3.19 Å3/Da / Density % sol: 61.43 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 15% PEG 6k 0.1M bicine 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 3, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.7→48.52 Å / Num. obs: 14673 / % possible obs: 100 % / Redundancy: 14 % / CC1/2: 0.999 / Net I/σ(I): 17.4
Reflection shellResolution: 2.7→2.83 Å / Num. unique obs: 1953 / CC1/2: 0.76

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
Aimlessdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→46.38 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.893 / SU B: 25.856 / SU ML: 0.247 / Cross valid method: THROUGHOUT / ESU R: 0.489 / ESU R Free: 0.32 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26833 650 4.4 %RANDOM
Rwork0.20307 ---
obs0.20583 13999 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 76.141 Å2
Baniso -1Baniso -2Baniso -3
1--1.56 Å20 Å2-0 Å2
2---1.56 Å20 Å2
3---3.11 Å2
Refinement stepCycle: 1 / Resolution: 2.7→46.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2580 0 54 0 2634
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0122714
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162410
X-RAY DIFFRACTIONr_angle_refined_deg1.3521.6513693
X-RAY DIFFRACTIONr_angle_other_deg0.451.5955502
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2875333
X-RAY DIFFRACTIONr_dihedral_angle_2_deg8.72513
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.44410391
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0610.2400
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.023401
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02649
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_it4.6555.8061338
X-RAY DIFFRACTIONr_mcbond_other4.655.8071338
X-RAY DIFFRACTIONr_mcangle_it7.00410.4321670
X-RAY DIFFRACTIONr_mcangle_other7.00210.4351670
X-RAY DIFFRACTIONr_scbond_it5.0815.8271376
X-RAY DIFFRACTIONr_scbond_other4.8225.8381369
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.4110.6112012
X-RAY DIFFRACTIONr_long_range_B_refined10.01253.993012
X-RAY DIFFRACTIONr_long_range_B_other10.01153.993013
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.425 56 -
Rwork0.319 1037 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -21.6739 Å / Origin y: 23.6109 Å / Origin z: 0.4503 Å
111213212223313233
T0.1106 Å20.0584 Å2-0.0349 Å2-0.0854 Å2-0.0521 Å2--0.0738 Å2
L1.7828 °20.3258 °2-0.4994 °2-3.1695 °2-0.7738 °2--3.8621 °2
S0.0306 Å °-0.0044 Å °-0.1461 Å °0.4323 Å °0.1414 Å °0.0824 Å °0.153 Å °-0.0983 Å °-0.1719 Å °

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