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- PDB-4kiq: Crystal structure of mitogen-activated protein kinase 14 (P38-H5)... -

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Basic information

Entry
Database: PDB / ID: 4kiq
TitleCrystal structure of mitogen-activated protein kinase 14 (P38-H5) complex with ETHYL 6-((5-(CYCLOPROPYLCARBAMOYL)-2-METHYLPHENYL)CARBAMOYL)-1H-INDOLE-1-CARBOXYLATE
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / SERINE/THREONINE-PROTEIN KINASE / KINASE / TRANSFERASE / P38 MAP KINASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / D-glucose import / p38MAPK cascade / ERK/MAPK targets / fatty acid oxidation / response to dietary excess / cellular response to lipoteichoic acid / response to muramyl dipeptide / MAP kinase kinase activity / Regulation of MITF-M-dependent genes involved in pigmentation / signal transduction in response to DNA damage / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / RHO GTPases Activate NADPH Oxidases / mitogen-activated protein kinase / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / negative regulation of hippo signaling / positive regulation of myoblast differentiation / stress-activated MAPK cascade / skeletal muscle tissue development / positive regulation of cardiac muscle cell proliferation / p38MAPK events / positive regulation of brown fat cell differentiation / response to muscle stretch / striated muscle cell differentiation / positive regulation of interleukin-12 production / positive regulation of erythrocyte differentiation / osteoclast differentiation / lipopolysaccharide-mediated signaling pathway / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / positive regulation of D-glucose import / cellular response to ionizing radiation / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / response to insulin / bone development / cellular response to virus / platelet activation / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / cell morphogenesis / chemotaxis / spindle pole / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / MAPK cascade / cellular response to lipopolysaccharide / angiogenesis / secretory granule lumen / protein phosphatase binding / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / transcription by RNA polymerase II / cell surface receptor signaling pathway / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / glutamatergic synapse / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular region / nucleoplasm / ATP binding
Similarity search - Function
Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-1RA / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsSack, J.S. / Tokarski, J.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: The Identification of Novel P38-Alpha Isoform Selective Kinase Inhibitors Having an Unprecedented P38-Alpha Binding Mode
Authors: Wrobleski, S.T. / Lin, S. / Murali Dhar, T.G. / Dyckman, A.J. / Li, T. / Pitt, S. / Zhang, R. / Fan, Y. / Doweyko, A.M. / Tokarski, J.S. / Kish, K.F. / Kiefer, S.E. / Sack, J.S. / Newitt, J. ...Authors: Wrobleski, S.T. / Lin, S. / Murali Dhar, T.G. / Dyckman, A.J. / Li, T. / Pitt, S. / Zhang, R. / Fan, Y. / Doweyko, A.M. / Tokarski, J.S. / Kish, K.F. / Kiefer, S.E. / Sack, J.S. / Newitt, J.A. / Witmer, M.R. / McKinnon, M. / Barrish, J.C. / Dodd, J.H. / Schieven, G.L. / Leftheris, K.
History
DepositionMay 2, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 12, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2013Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 14
B: Mitogen-activated protein kinase 14
C: Mitogen-activated protein kinase 14
D: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,0428
Polymers168,4204
Non-polymers1,6224
Water8,161453
1
A: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5102
Polymers42,1051
Non-polymers4051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5102
Polymers42,1051
Non-polymers4051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5102
Polymers42,1051
Non-polymers4051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5102
Polymers42,1051
Non-polymers4051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.002, 73.539, 100.574
Angle α, β, γ (deg.)90.00, 96.66, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Mitogen-activated protein kinase 14 / MAP kinase 14 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID- ...MAP kinase 14 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID-binding protein / CSBP / MAP kinase MXI2 / MAX-interacting protein 2 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Stress-activated protein kinase 2a / SAPK2a


Mass: 42105.004 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSBP, CSBP1, CSBP2, CSPB1, MAPK14, MXI2, SAPK2A / Cell line (production host): BL21 DE3 / Production host: Escherichia coli (E. coli)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical
ChemComp-1RA / ethyl 6-{[5-(cyclopropylcarbamoyl)-2-methylphenyl]carbamoyl}-1H-indole-1-carboxylate


Mass: 405.446 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H23N3O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 453 / 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: 2.2 Å3/Da / Density % sol: 44.16 %
Crystal growpH: 6
Details: 1-6% (W/V) PEG-4K 50 MM MES, PH 6.0, 5MM MAGNESIUM SULFATE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 14, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 49302 / % possible obs: 96.5 % / Observed criterion σ(I): 0 / Redundancy: 2.5 % / Biso Wilson estimate: 48.24 Å2 / Rmerge(I) obs: 0.022 / Net I/σ(I): 39.2
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.058 / Mean I/σ(I) obs: 15.6 / % possible all: 95.7

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3S4Q

3s4q


Resolution: 2.5→42.88 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.8964 / SU R Cruickshank DPI: 0.874 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.228 2489 5.05 %RANDOM
Rwork0.1839 ---
obs0.1861 49257 96.61 %-
Displacement parametersBiso mean: 39.52 Å2
Baniso -1Baniso -2Baniso -3
1--0.4408 Å20 Å22.4259 Å2
2--1.2695 Å20 Å2
3----0.8288 Å2
Refine analyzeLuzzati coordinate error obs: 0.281 Å
Refinement stepCycle: LAST / Resolution: 2.5→42.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10880 0 120 453 11453
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111268HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1115308HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3932SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes280HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1700HARMONIC5
X-RAY DIFFRACTIONt_it11268HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.97
X-RAY DIFFRACTIONt_other_torsion18.52
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1448SEMIHARMONIC5
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_contact12984SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.56 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2813 189 5.29 %
Rwork0.21 3382 -
all0.2139 3571 -
obs--96.61 %

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