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- PDB-9r59: Crystal structure of MAPKAPK2 with a covalent compound GCL334 tar... -

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Basic information

Entry
Database: PDB / ID: 9r59
TitleCrystal structure of MAPKAPK2 with a covalent compound GCL334 targeting lysine
ComponentsMAP kinase-activated protein kinase 2
KeywordsTRANSFERASE / kinase / covalent inhibitor / lysine / MAPKAPK2
Function / homology
Function and homology information


calcium-dependent protein serine/threonine kinase activity / CREB phosphorylation / macropinocytosis / Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA / leukotriene metabolic process / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / Synthesis of Leukotrienes (LT) and Eoxins (EX) / regulation of tumor necrosis factor production / regulation of tumor necrosis factor-mediated signaling pathway / calcium/calmodulin-dependent protein kinase activity ...calcium-dependent protein serine/threonine kinase activity / CREB phosphorylation / macropinocytosis / Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA / leukotriene metabolic process / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / Synthesis of Leukotrienes (LT) and Eoxins (EX) / regulation of tumor necrosis factor production / regulation of tumor necrosis factor-mediated signaling pathway / calcium/calmodulin-dependent protein kinase activity / regulation of interleukin-6 production / mitogen-activated protein kinase binding / positive regulation of macrophage cytokine production / 3'-UTR-mediated mRNA stabilization / toll-like receptor signaling pathway / p38MAPK cascade / inner ear development / cellular response to vascular endothelial growth factor stimulus / Regulation of HSF1-mediated heat shock response / vascular endothelial growth factor receptor signaling pathway / regulation of cellular response to heat / p38MAPK events / response to cytokine / regulation of mRNA stability / activated TAK1 mediates p38 MAPK activation / Regulation of TNFR1 signaling / VEGFA-VEGFR2 Pathway / positive regulation of tumor necrosis factor production / MAPK cascade / Oxidative Stress Induced Senescence / response to lipopolysaccharide / calmodulin binding / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / ciliary basal body / inflammatory response / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / DNA damage response / extracellular exosome / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
MAP kinase activated protein kinase, C-terminal / 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
: / MAP kinase-activated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsWang, G.Q. / Hillebrand, L. / Gehringer, M. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support Canada, 1items
OrganizationGrant numberCountry
The Structural Genomics Consortium (SGC) Canada
CitationJournal: To Be Published
Title: Crystal structure of MAPKAPK2 with a covalent compound GCL334 targeting lysine
Authors: Wang, G.Q. / Hillebrand, L. / Gehringer, M. / Knapp, S. / Structural Genomics Consortium (SGC)
History
DepositionMay 8, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 30, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: MAP kinase-activated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4752
Polymers36,9041
Non-polymers5711
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.745, 102.745, 167.683
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number182
Space group name H-MP6322

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Components

#1: Protein MAP kinase-activated protein kinase 2 / MAPK-activated protein kinase 2 / MAPKAP kinase 2 / MAPKAP-K2 / MAPKAPK-2 / MK-2 / MK2


Mass: 36903.703 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPKAPK2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P49137, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A1JH4 / 5-[3-[bis(oxidanyl)-$l^{3}-sulfanyl]oxy-4-chloranyl-phenyl]-~{N}-(4-piperazin-1-ylphenyl)-~{N}-(pyridin-2-ylmethyl)furan-2-carboxamide


Mass: 571.044 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C27H27ClN4O6S / Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli BL21(DE3) (bacteria) / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.69 Å3/Da / Density % sol: 66.69 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: 1M succinic acid, 1% PEG2000 MME, 0.1M HEPES pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.976269 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jul 1, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976269 Å / Relative weight: 1
ReflectionResolution: 3→51.37 Å / Num. obs: 11099 / % possible obs: 99.9 % / Redundancy: 38.7 % / CC1/2: 0.984 / Net I/σ(I): 6.9
Reflection shellResolution: 3→3.18 Å / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1741 / CC1/2: 0.733

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
PDB_EXTRACTdata extraction
DIALSdata reduction
DIALSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→49.17 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.906 / SU B: 14.23 / SU ML: 0.25 / Cross valid method: THROUGHOUT / ESU R: 0.795 / ESU R Free: 0.326 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.22901 570 5.1 %RANDOM
Rwork0.20063 ---
obs0.20214 10501 99.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.933 Å2
Baniso -1Baniso -2Baniso -3
1--1.24 Å2-0.62 Å2-0 Å2
2---1.24 Å2-0 Å2
3---4.01 Å2
Refinement stepCycle: 1 / Resolution: 3→49.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2266 0 0 12 2278
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0122323
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162164
X-RAY DIFFRACTIONr_angle_refined_deg1.7211.8343144
X-RAY DIFFRACTIONr_angle_other_deg0.5681.7875003
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.5395278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg13.994514
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.54210406
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0760.2346
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022759
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02518
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_it3.3633.8651124
X-RAY DIFFRACTIONr_mcbond_other3.3613.8651124
X-RAY DIFFRACTIONr_mcangle_it5.4656.9281398
X-RAY DIFFRACTIONr_mcangle_other5.4636.9271399
X-RAY DIFFRACTIONr_scbond_it3.6514.1911199
X-RAY DIFFRACTIONr_scbond_other3.654.191200
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.9847.5631747
X-RAY DIFFRACTIONr_long_range_B_refined9.96346.149812
X-RAY DIFFRACTIONr_long_range_B_other9.96346.149813
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 37 -
Rwork0.264 764 -
obs--100 %

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