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- PDB-3kc3: MK2 complexed to inhibitor N4-(7-(benzofuran-2-yl)-1H-indazol-5-y... -

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Basic information

Entry
Database: PDB / ID: 3kc3
TitleMK2 complexed to inhibitor N4-(7-(benzofuran-2-yl)-1H-indazol-5-yl)pyrimidine-2,4-diamine
ComponentsMAP kinase-activated protein kinase 2
KeywordsTRANSFERASE / MAPKAP-K2 / MK2 / TNFalpha / diaminopyrimidine / ATP-binding / Kinase / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase
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 / calmodulin-dependent protein kinase activity / mitogen-activated protein kinase binding ...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 / calmodulin-dependent protein kinase activity / mitogen-activated protein kinase binding / positive regulation of macrophage cytokine production / regulation of interleukin-6 production / toll-like receptor signaling pathway / 3'-UTR-mediated mRNA stabilization / p38MAPK cascade / inner ear development / regulation of cellular response to heat / Regulation of HSF1-mediated heat shock response / vascular endothelial growth factor receptor signaling pathway / cellular response to vascular endothelial growth factor stimulus / regulation of mRNA stability / p38MAPK events / response to cytokine / activated TAK1 mediates p38 MAPK activation / VEGFA-VEGFR2 Pathway / positive regulation of tumor necrosis factor production / MAPK cascade / Oxidative Stress Induced Senescence / calmodulin binding / response to lipopolysaccharide / non-specific serine/threonine protein kinase / peptidyl-serine phosphorylation / intracellular signal transduction / protein kinase activity / inflammatory response / protein autophosphorylation / centrosome / protein serine kinase activity / DNA damage response / protein serine/threonine kinase activity / protein phosphorylation / 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. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain / Phosphorylase Kinase; domain 1 / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...MAP kinase activated protein kinase, C-terminal / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain / Phosphorylase Kinase; domain 1 / 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-MK2 / MAP kinase-activated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsArgiriadi, M.A. / Talanian, R.V. / Borhani, D.W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: 2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode.
Authors: Argiriadi, M.A. / Ericsson, A.M. / Harris, C.M. / Banach, D.L. / Borhani, D.W. / Calderwood, D.J. / Demers, M.D. / Dimauro, J. / Dixon, R.W. / Hardman, J. / Kwak, S. / Li, B. / Mankovich, J. ...Authors: Argiriadi, M.A. / Ericsson, A.M. / Harris, C.M. / Banach, D.L. / Borhani, D.W. / Calderwood, D.J. / Demers, M.D. / Dimauro, J. / Dixon, R.W. / Hardman, J. / Kwak, S. / Li, B. / Mankovich, J.A. / Marcotte, D. / Mullen, K.D. / Ni, B. / Pietras, M. / Sadhukhan, R. / Sousa, S. / Tomlinson, M.J. / Wang, L. / Xiang, T. / Talanian, R.V.
History
DepositionOct 20, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance

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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
G: MAP kinase-activated protein kinase 2
H: MAP kinase-activated protein kinase 2
I: MAP kinase-activated protein kinase 2
J: MAP kinase-activated protein kinase 2
K: MAP kinase-activated protein kinase 2
L: MAP kinase-activated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)454,02223
Polymers450,25612
Non-polymers3,76611
Water36020
1
A: MAP kinase-activated protein kinase 2
F: MAP kinase-activated protein kinase 2
H: MAP kinase-activated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,5916
Polymers112,5643
Non-polymers1,0273
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5840 Å2
ΔGint-28 kcal/mol
Surface area42250 Å2
MethodPISA
2
B: MAP kinase-activated protein kinase 2
E: MAP kinase-activated protein kinase 2
J: MAP kinase-activated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,5916
Polymers112,5643
Non-polymers1,0273
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5960 Å2
ΔGint-26 kcal/mol
Surface area41600 Å2
MethodPISA
3
C: MAP kinase-activated protein kinase 2
I: MAP kinase-activated protein kinase 2
L: MAP kinase-activated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,5916
Polymers112,5643
Non-polymers1,0273
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5870 Å2
ΔGint-26 kcal/mol
Surface area42860 Å2
MethodPISA
4
D: MAP kinase-activated protein kinase 2
G: MAP kinase-activated protein kinase 2
K: MAP kinase-activated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,2495
Polymers112,5643
Non-polymers6852
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4600 Å2
ΔGint-21 kcal/mol
Surface area41050 Å2
MethodPISA
5


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area42480 Å2
ΔGint-182 kcal/mol
Surface area147560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)139.351, 179.793, 214.376
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Details1

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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: 37521.332 Da / Num. of mol.: 12 / Fragment: Kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPKAPK2 / Plasmid: pGEX4T-1 / Production host: Escherichia coli (E. coli)
References: UniProt: P49137, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-MK2 / N~4~-[7-(1-benzofuran-2-yl)-1H-indazol-5-yl]pyrimidine-2,4-diamine / N4-[7-(1-benzofuran-2-yl)-1H-indazol-5-yl]pyrimidine-2,4-diamine


Mass: 342.354 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C19H14N6O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 2.98 Å3/Da / Density % sol: 58.76 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 1.75 M Ammonium Sulfate, 0.1 M Na Citrate, pH 8.0., VAPOR DIFFUSION, SITTING DROP, temperature 291.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: 2005
RadiationMonochromator: Si(111) double-crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 116686 / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.6 % / Rsym value: 0.093 / Net I/σ(I): 27
Reflection shellResolution: 2.9→3 Å / Redundancy: 2.6 % / Mean I/σ(I) obs: 3.83 / Num. unique all: 10342 / Rsym value: 0.401

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→20 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.864 / SU B: 34.996 / SU ML: 0.317 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R Free: 0.448 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29759 5825 5 %RANDOM
Rwork0.22987 ---
obs0.23324 110192 97.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 66.829 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å20 Å20 Å2
2---0.05 Å20 Å2
3----0.02 Å2
Refinement stepCycle: LAST / Resolution: 2.9→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms27853 0 286 20 28159
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.02228789
X-RAY DIFFRACTIONr_angle_refined_deg1.9281.98138834
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.38753383
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.76723.8871294
X-RAY DIFFRACTIONr_dihedral_angle_3_deg22.769155373
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.86715197
X-RAY DIFFRACTIONr_chiral_restr0.1230.24201
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0221931
X-RAY DIFFRACTIONr_nbd_refined0.2650.213919
X-RAY DIFFRACTIONr_nbtor_refined0.3280.219291
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1810.21021
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3680.2102
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3940.28
X-RAY DIFFRACTIONr_mcbond_it1.0351.517612
X-RAY DIFFRACTIONr_mcangle_it1.808227829
X-RAY DIFFRACTIONr_scbond_it2.169312824
X-RAY DIFFRACTIONr_scangle_it3.5964.511005
LS refinement shellResolution: 2.9→2.974 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.381 349 -
Rwork0.28 6778 -
obs--83.22 %
Refinement TLS params.Method: refined / Origin x: -17.026 Å / Origin y: 11.682 Å / Origin z: -26.966 Å
111213212223313233
T-0.0987 Å2-0.0403 Å20.0184 Å2-0.0078 Å2-0.046 Å2--0.002 Å2
L0.1428 °2-0.0842 °2-0.0439 °2-0.2034 °20.067 °2--0.1644 °2
S0.0298 Å °0.0115 Å °-0.0366 Å °-0.0327 Å °-0.0551 Å °0.0458 Å °0.069 Å °-0.0442 Å °0.0253 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A43 - 138
2X-RAY DIFFRACTION1A139 - 347
3X-RAY DIFFRACTION1B44 - 138
4X-RAY DIFFRACTION1B139 - 349
5X-RAY DIFFRACTION1C41 - 138
6X-RAY DIFFRACTION1C139 - 345
7X-RAY DIFFRACTION1D46 - 138
8X-RAY DIFFRACTION1D139 - 342
9X-RAY DIFFRACTION1E44 - 138
10X-RAY DIFFRACTION1E139 - 345
11X-RAY DIFFRACTION1F44 - 138
12X-RAY DIFFRACTION1F139 - 350
13X-RAY DIFFRACTION1G43 - 138
14X-RAY DIFFRACTION1G139 - 342
15X-RAY DIFFRACTION1H44 - 138
16X-RAY DIFFRACTION1H139 - 350
17X-RAY DIFFRACTION1I45 - 138
18X-RAY DIFFRACTION1I139 - 356
19X-RAY DIFFRACTION1J43 - 138
20X-RAY DIFFRACTION1J139 - 348
21X-RAY DIFFRACTION1K44 - 138
22X-RAY DIFFRACTION1K139 - 345
23X-RAY DIFFRACTION1L42 - 138
24X-RAY DIFFRACTION1L139 - 348

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