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- PDB-2jbp: Protein kinase MK2 in complex with an inhibitor (crystal form-2, ... -

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Basic information

Entry
Database: PDB / ID: 2jbp
TitleProtein kinase MK2 in complex with an inhibitor (crystal form-2, co- crystallization)
ComponentsMAP KINASE-ACTIVATED PROTEIN KINASE 2
KeywordsTRANSFERASE / SER-THR KINASE / MAPKAP KINASE 2 / PHOSPHORYLATION / SMALL MOLECULE INHIBITOR / MK2 / KINASE / ATP SITE / ATP- BINDING / SERINE/THREONINE-PROTEIN KINASE / CO-CRYSTALLIZATION / NUCLEOTIDE-BINDING
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-mediated signaling pathway / regulation of tumor necrosis factor production / 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-mediated signaling pathway / regulation of tumor necrosis factor production / 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 / centrosome / protein serine/threonine kinase activity / DNA damage response / extracellular exosome / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
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-P4O / MAP kinase-activated protein kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.31 Å
AuthorsHillig, R.C. / Eberspaecher, U. / Monteclaro, F. / Huber, M. / Nguyen, D. / Mengel, A. / Muller-Tiemann, B. / Egner, U.
Citation
Journal: J. Mol. Biol. / Year: 2007
Title: Structural basis for a high affinity inhibitor bound to protein kinase MK2.
Authors: Hillig, R.C. / Eberspaecher, U. / Monteclaro, F. / Huber, M. / Nguyen, D. / Mengel, A. / Muller-Tiemann, B. / Egner, U.
#1: Journal: Protein Sci. / Year: 2006
Title: Identifying Protein Construct Variants with Increased Crystallization Propensity-A Case Study.
Authors: Malawski, G.A. / Hillig, R.C. / Monteclaro, F. / Eberspaecher, U. / Schmitz, A.A. / Crusius, K. / Huber, M. / Egner, U. / Donner, P. / Muller-Tiemann, B.
History
DepositionDec 9, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 20, 2007Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jan 16, 2019Group: Data collection / Database references / Derived calculations
Category: citation / pdbx_struct_assembly
Item: _citation.journal_abbrev / _citation.page_last ..._citation.journal_abbrev / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details
Revision 1.4Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)455,73023
Polymers451,98612
Non-polymers3,74411
Water32418
1
A: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
G: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
H: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
9
I: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
10
J: MAP KINASE-ACTIVATED PROTEIN KINASE 2


Theoretical massNumber of molelcules
Total (without water)37,6651
Polymers37,6651
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
11
K: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
12
L: MAP KINASE-ACTIVATED PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0062
Polymers37,6651
Non-polymers3401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)139.983, 215.564, 179.900
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1, -0.00115, 0.0006), (0.00079, 0.17309, -0.98491), (0.00103, 0.98491, 0.17309)-34.32618, 114.38394, 5.41508
2given(-0.28969, 0.68298, 0.67054), (0.48575, 0.49874, -0.71785), (0.8247, -0.53367, 0.18728)-96.82758, 81.23378, 251.45364
3given(-0.28593, 0.68395, 0.67116), (-0.90129, -0.42983, 0.05405), (0.32545, -0.58946, 0.73934)-62.80188, 236.4353, 76.47049
4given(-0.30881, -0.86636, 0.39251), (0.65031, -0.49347, -0.57756), (0.69407, 0.0769, 0.71579)160.71569, 199.05609, -30.26304
5given(0.83266, -0.43253, 0.34582), (-0.4166, -0.0778, 0.90576), (-0.36486, -0.89826, -0.24497)12.84003, 61.06001, 299.58054
6given(-0.29922, -0.49918, 0.8132), (0.67525, 0.49137, 0.55008), (-0.67417, 0.71371, 0.19004)53.6608, -51.66178, 75.7632
7given(0.29421, 0.51778, 0.80334), (0.48381, -0.80557, 0.34203), (0.82424, 0.28803, -0.48751)-113.30266, 144.70901, 92.36734
8given(-0.28531, -0.509, 0.81211), (-0.52875, 0.79031, 0.30957), (-0.79939, -0.34108, -0.49462)89.16364, 38.25184, 172.51189
9given(-0.81106, 0.44616, -0.37832), (0.44081, 0.89131, 0.10611), (0.38454, -0.08071, -0.91957)21.79391, -67.84104, 190.14537
10given(0.28722, 0.5145, 0.80796), (-0.89824, -0.14828, 0.41373), (0.33267, -0.84457, 0.41956)-147.51453, 16.39386, 195.57885
11given(-0.27864, -0.88779, 0.36632), (-0.54247, -0.16927, -0.82285), (0.79252, -0.428, -0.43443)129.64796, 179.58492, 187.43855

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Components

#1: Protein
MAP KINASE-ACTIVATED PROTEIN KINASE 2 / MAPKAP KINASE 2 / MAPK-ACTIVATED PROTEIN KINASE 2 / MAPKAPK-2 / MK2


Mass: 37665.461 Da / Num. of mol.: 12 / Fragment: KINASE DOMAIN, RESIDUES 41-364
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21
References: UniProt: P49137, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-P4O / 2-(2-QUINOLIN-3-YLPYRIDIN-4-YL)-1,5,6,7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONE


Mass: 340.378 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C21H16N4O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 18 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details2-(QUINOLIN-3-YLPYRIDIN-4-YL)-1,5,6, 7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONE (P4O): PROTEIN ...2-(QUINOLIN-3-YLPYRIDIN-4-YL)-1,5,6, 7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONE (P4O): PROTEIN CHAIN J HAS NO LIGAND BOUND IN THE ACTIVE SITE, THEREFORE THERE IS NO LIGAND J, AND IN TOTAL THERE ARE ONLY 11 LIGAND MOLECULES.
Sequence detailsN-TERMINAL RESIDUES GLY-SER ARE CLONING ARTEFACTS FROM A THROMBIN CLEAVAGE SITE, AFTER GST TAG CLEAVAGE.

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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 Å3/Da / Density % sol: 59.1 %
Description: MOLREP IDENTIFIED 11 MOLECULES. AFTER SOME REBUILDING AND REFINEMENT, BEAST IDENTIFIED THE TWELTH MOLECULE.
Crystal growpH: 7.5
Details: 1.8-2.0M SODIUM POTTASIUM PHOSPHATE PH 7.5, 0.0003M INHIBITOR

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.979
DetectorType: MARRESEARCH / Detector: CCD / Date: Apr 28, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.3→49.1 Å / Num. obs: 78680 / % possible obs: 97 % / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 96.4 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 12.8
Reflection shellResolution: 3.3→3.38 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.6 / Mean I/σ(I) obs: 2 / % possible all: 95.1

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
BEASTphasing
CNX2005refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2JBO

2jbo


Resolution: 3.31→49.08 Å / Rfactor Rfree error: 0.004 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
Details: IN THE CRYSTAL LATTICE, THE TWELVE MK2 MOLECULES FORM FOUR TRIMERS OF TYPE-1, VIA N-TERMINI, AND THREE TRIMERS OF TYPE-2, VIA ACTIVATION SEGMENTS. THE ACTIVATION SEGMENTS INCLUDE RESIDUES ...Details: IN THE CRYSTAL LATTICE, THE TWELVE MK2 MOLECULES FORM FOUR TRIMERS OF TYPE-1, VIA N-TERMINI, AND THREE TRIMERS OF TYPE-2, VIA ACTIVATION SEGMENTS. THE ACTIVATION SEGMENTS INCLUDE RESIDUES 207 - 233 AND ARE PARTIALLY DISORDERED.
RfactorNum. reflection% reflectionSelection details
Rfree0.279 3911 5 %RANDOM
Rwork0.215 ---
obs-78629 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 58.2952 Å2 / ksol: 0.311991 e/Å3
Displacement parametersBiso mean: 82.2 Å2
Baniso -1Baniso -2Baniso -3
1-3.04 Å20 Å20 Å2
2--8.32 Å20 Å2
3----11.37 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.42 Å0.28 Å
Luzzati d res low-5 Å
Luzzati sigma a0.57 Å0.44 Å
Refinement stepCycle: LAST / Resolution: 3.31→49.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms27063 0 286 18 27367
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.017
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.7
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d24.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d1.08
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it8.772
X-RAY DIFFRACTIONc_mcangle_it13.183
X-RAY DIFFRACTIONc_scbond_it18.134.5
X-RAY DIFFRACTIONc_scangle_it22.156
Refine LS restraints NCSNCS model details: RESTRAINTS
LS refinement shellResolution: 3.3→3.42 Å / Rfactor Rfree error: 0.024 / Total num. of bins used: 10
Rfactor% reflection
Rfree0.429 5.1 %
Rwork0.361 -
obs-79.4 %
Xplor fileSerial no: 1 / Param file: PROTEIN_REP.PARAM / Topol file: DRGCNS.TOP

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