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- PDB-3m2w: Crystal structure of MAPKAK kinase 2 (MK2) complexed with a spiro... -

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Basic information

Entry
Database: PDB / ID: 3m2w
TitleCrystal structure of MAPKAK kinase 2 (MK2) complexed with a spiroazetidine-tetracyclic ATP site inhibitor
ComponentsMAP kinase-activated protein kinase 2
KeywordsTRANSFERASE / SMALL MOLECULE INHIBITOR / spiroazetidine-tetracycle / ATP-SITE KINASE INHIBITOR / NOVARTIS compound NVP-BXS169 / ATP-binding / Kinase / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase
Function / homology
Function and homology information


macropinocytosis / CREB phosphorylation / 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) / calcium-dependent protein serine/threonine kinase activity / regulation of tumor necrosis factor production / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of macrophage cytokine production ...macropinocytosis / CREB phosphorylation / 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) / calcium-dependent protein serine/threonine kinase activity / regulation of tumor necrosis factor production / regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of macrophage cytokine production / mitogen-activated protein kinase binding / regulation of interleukin-6 production / calcium/calmodulin-dependent protein kinase activity / 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 / positive regulation of tumor necrosis factor production / MAPK cascade / peptidyl-serine phosphorylation / Oxidative Stress Induced Senescence / response to lipopolysaccharide / non-specific serine/threonine protein kinase / calmodulin binding / 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 / cytoplasm / cytosol
Similarity search - Function
MAP kinase activated protein kinase, C-terminal / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 ...MAP kinase activated protein kinase, C-terminal / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-L8I / MAP kinase-activated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.41 Å
AuthorsKroemer, M. / Revesz, L. / Be, C. / Izaac, A. / Huppertz, C. / Schlapbach, A. / Scheufler, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part II.
Authors: Revesz, L. / Schlapbach, A. / Aichholz, R. / Dawson, J. / Feifel, R. / Hawtin, S. / Littlewood-Evans, A. / Koch, G. / Kroemer, M. / Mobitz, H. / Scheufler, C. / Velcicky, J. / Huppertz, C.
History
DepositionMar 8, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 28, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 6, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)34,9773
Polymers34,5641
Non-polymers4132
Water2,432135
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)102.982, 102.982, 165.433
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number182
Space group name H-MP6322
Components on special symmetry positions
IDModelComponents
11A-3-

HOH

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Components

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


Mass: 34564.043 Da / Num. of mol.: 1 / Fragment: Kinase domain / Mutation: DELTA216-236, P237G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPKAPK2 / Plasmid: PET / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)TUNER
References: UniProt: P49137, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-L8I / 2'-(2-fluorophenyl)-1-methyl-6',8',9',11'-tetrahydrospiro[azetidine-3,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one


Mass: 388.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21FN4O
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 135 / 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: 3.66 Å3/Da / Density % sol: 66.42 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.3
Details: 0.1M BICINE, 1.3M SODIUM MALONATE, pH 8.3, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00014 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jan 24, 2008
RadiationMonochromator: SAGITALLY FOCUSED SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00014 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. obs: 20549 / % possible obs: 97.9 % / Redundancy: 11.7 % / Biso Wilson estimate: 34 Å2 / Rmerge(I) obs: 0.13 / Net I/σ(I): 18
Reflection shellResolution: 2.4→2.51 Å / Redundancy: 11.6 % / Rmerge(I) obs: 0.582 / Mean I/σ(I) obs: 4.5 / Num. unique all: 2257 / % possible all: 84.9

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Processing

Software
NameVersionClassification
REFMAC5.5.0102refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.41→29.26 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.911 / SU B: 5.503 / SU ML: 0.129 / Cross valid method: THROUGHOUT / ESU R: 0.236 / ESU R Free: 0.201 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22685 1028 5 %RANDOM
Rwork0.18513 ---
obs0.18723 19521 99.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.937 Å2
Baniso -1Baniso -2Baniso -3
1--0.41 Å2-0.2 Å20 Å2
2---0.41 Å20 Å2
3---0.61 Å2
Refinement stepCycle: LAST / Resolution: 2.41→29.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2274 0 30 135 2439
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222445
X-RAY DIFFRACTIONr_bond_other_d00.021673
X-RAY DIFFRACTIONr_angle_refined_deg1.3841.9823311
X-RAY DIFFRACTIONr_angle_other_deg0.7934059
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9395306
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.07423.68495
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.54615429
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.6761515
X-RAY DIFFRACTIONr_chiral_restr0.0780.2367
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212693
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02476
X-RAY DIFFRACTIONr_mcbond_it1.45921530
X-RAY DIFFRACTIONr_mcbond_other0.3222618
X-RAY DIFFRACTIONr_mcangle_it2.73132456
X-RAY DIFFRACTIONr_scbond_it4.0444.5915
X-RAY DIFFRACTIONr_scangle_it5.8776853
LS refinement shellResolution: 2.41→2.475 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.292 71 -
Rwork0.233 1344 -
obs-1344 95.22 %

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