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- PDB-6t8x: Crystal structure of MAPKAPK2 (MK2) complexed with PF-3644022 and... -

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Basic information

Entry
Database: PDB / ID: 6t8x
TitleCrystal structure of MAPKAPK2 (MK2) complexed with PF-3644022 and 5-(4-bromophenyl)-N-[4-(1-piperazinyl)phenyl]-N-(2-pyridinylmethyl)-2-furancarboxamide
ComponentsMAP kinase-activated protein kinase 2
KeywordsIMMUNE SYSTEM / kinase / non-ATP competitive inhibitor / type4
Function / homology
Function and homology information


macropinocytosis / CREB phosphorylation / calcium-dependent protein serine/threonine kinase activity / Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / leukotriene metabolic process / Synthesis of Leukotrienes (LT) and Eoxins (EX) / regulation of tumor necrosis factor production / regulation of tumor necrosis factor-mediated signaling pathway / calmodulin-dependent protein kinase activity ...macropinocytosis / CREB phosphorylation / calcium-dependent protein serine/threonine kinase activity / Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / leukotriene metabolic process / Synthesis of Leukotrienes (LT) and Eoxins (EX) / regulation of tumor necrosis factor production / regulation of tumor necrosis factor-mediated signaling pathway / calmodulin-dependent protein kinase activity / positive regulation of macrophage cytokine production / mitogen-activated protein kinase binding / regulation of interleukin-6 production / 3'-UTR-mediated mRNA stabilization / toll-like receptor signaling pathway / p38MAPK cascade / inner ear development / Regulation of HSF1-mediated heat shock response / cellular response to vascular endothelial growth factor stimulus / vascular endothelial growth factor receptor signaling pathway / regulation of cellular response to heat / p38MAPK events / regulation of mRNA stability / response to cytokine / activated TAK1 mediates p38 MAPK activation / Regulation of TNFR1 signaling / VEGFA-VEGFR2 Pathway / MAPK cascade / positive regulation of tumor necrosis factor production / peptidyl-serine phosphorylation / Oxidative Stress Induced Senescence / response to lipopolysaccharide / calmodulin binding / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / inflammatory response / protein phosphorylation / 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
Chem-B97 / Chem-MW8 / MAP kinase-activated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsBeaumont, E.J. / Barker, J.
CitationJournal: To Be Published
Title: Crystal structure of MAPKAPK2 (MK2) complexed with PF-3644022 and 5-(4-bromophenyl)-N-[4-(1-piperazinyl)phenyl]-N-(2-pyridinylmethyl)-2-furancarboxamide
Authors: Beaumont, E.J. / Barker, J.
History
DepositionOct 25, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 12, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 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

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Assembly

Deposited unit
A: MAP kinase-activated protein kinase 2
B: MAP kinase-activated protein kinase 2
C: MAP kinase-activated protein kinase 2
D: MAP kinase-activated protein kinase 2
E: MAP kinase-activated protein kinase 2
F: MAP kinase-activated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)226,43824
Polymers220,8746
Non-polymers5,56418
Water63135
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area16380 Å2
ΔGint-135 kcal/mol
Surface area76410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)131.531, 287.339, 148.407
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein
MAP kinase-activated protein kinase 2 / MK2


Mass: 36812.258 Da / Num. of mol.: 6 / Mutation: T222E, T334E
Source method: isolated from a genetically manipulated source
Details: B97 and 5-(4-bromophenyl)-N-[4-(1-piperazinyl)phenyl]-N-(2-pyridinylmethyl)-2-furancarboxamide
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-B97 / (10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one


Mass: 374.459 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C21H18N4OS
#3: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Cl
#4: Chemical
ChemComp-MW8 / 5-(4-bromophenyl)-~{N}-(4-piperazin-1-ylphenyl)-~{N}-(pyridin-2-ylmethyl)furan-2-carboxamide


Mass: 517.417 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C27H25BrN4O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 35 / 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: 3.39 Å3/Da / Density % sol: 63.74 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 1.3M NaMalonate, 0.1M Hepes pH6.0, 0.5% jeffamine ED2003

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.81→143.67 Å / Num. obs: 68678 / % possible obs: 100 % / Redundancy: 6.1 % / CC1/2: 0.998 / Rmerge(I) obs: 0.083 / Rrim(I) all: 0.1 / Net I/σ(I): 10.6
Reflection shellResolution: 2.81→2.88 Å / Redundancy: 6.2 % / Rmerge(I) obs: 1.495 / Mean I/σ(I) obs: 1 / Num. unique obs: 28351 / CC1/2: 0.668 / % possible all: 99.7

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (3-OCT-2019)refinement
xia2data reduction
PDB_EXTRACT3.25data extraction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1NY3

1ny3


Resolution: 2.81→120 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.907 / SU R Cruickshank DPI: 0.66 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.603 / SU Rfree Blow DPI: 0.302 / SU Rfree Cruickshank DPI: 0.312
RfactorNum. reflection% reflectionSelection details
Rfree0.2472 3441 5.02 %RANDOM
Rwork0.2277 ---
obs0.2287 68521 99.8 %-
Displacement parametersBiso max: 146.62 Å2 / Biso mean: 92.85 Å2 / Biso min: 59.68 Å2
Baniso -1Baniso -2Baniso -3
1--31.8877 Å20 Å20 Å2
2--26.9223 Å20 Å2
3---4.9654 Å2
Refine analyzeLuzzati coordinate error obs: 0.45 Å
Refinement stepCycle: final / Resolution: 2.81→120 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13480 0 372 35 13887
Biso mean--107.34 74.07 -
Num. residues----1664
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4973SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes2460HARMONIC5
X-RAY DIFFRACTIONt_it14195HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1784SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact10382SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d14195HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg19183HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion2.72
X-RAY DIFFRACTIONt_other_torsion17.84
LS refinement shellResolution: 2.81→3 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3435 60 4.38 %
Rwork0.2808 1311 -
all0.2836 1371 -
obs--99.63 %

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