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- PDB-9mhb: Crystal Structure of Human P38 alpha MAPK In Complex with MW01-14... -

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Basic information

Entry
Database: PDB / ID: 9mhb
TitleCrystal Structure of Human P38 alpha MAPK In Complex with MW01-14-064SRM
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE/INHIBITOR / P38 alpha MAPK / MW01-14-064SRM / 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 / CD163 mediating an anti-inflammatory response / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA ...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 / CD163 mediating an anti-inflammatory response / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA / cartilage condensation / cellular response to UV-B / mitogen-activated protein kinase p38 binding / Platelet sensitization by LDL / positive regulation of muscle cell differentiation / 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 / Regulation of MITF-M-dependent genes involved in pigmentation / fatty acid oxidation / cellular response to lipoteichoic acid / response to dietary excess / response to muramyl dipeptide / MAP kinase kinase activity / JUN kinase activity / RHO GTPases Activate NADPH Oxidases / regulation of ossification / MAP kinase activity / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / mitogen-activated protein kinase / chondrocyte differentiation / negative regulation of hippo signaling / positive regulation of myoblast differentiation / vascular endothelial growth factor receptor signaling pathway / skeletal muscle tissue development / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / positive regulation of interleukin-12 production / osteoclast differentiation / lipopolysaccharide-mediated signaling pathway / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / cellular response to ionizing radiation / positive regulation of D-glucose import / response to insulin / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / placenta development / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / cell morphogenesis / bone development / platelet activation / cellular response to virus / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / spindle pole / chemotaxis / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / cellular senescence / peptidyl-serine phosphorylation / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / secretory granule lumen / protein phosphatase binding / Oxidative Stress Induced Senescence / angiogenesis / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / transcription by RNA polymerase II / cell surface receptor signaling pathway / nuclear speck / intracellular signal transduction / 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
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. / : / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase 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
: / ACETATE ION / 4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE / DI(HYDROXYETHYL)ETHER / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsMinasov, G. / Tokars, V.L. / Roy, S.M. / Watterson, D.M. / Shuvalova, L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG066722 United States
CitationJournal: To Be Published
Title: Crystal Structure of Human P38 alpha MAPK In Complex with MW01-14-064SRM
Authors: Minasov, G. / Tokars, V.L. / Roy, S.M. / Watterson, D.M. / Shuvalova, L.
History
DepositionDec 11, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)42,6528
Polymers41,5601
Non-polymers1,0917
Water5,819323
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.446, 74.862, 78.065
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#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: 41560.375 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2, SAPK2A / Plasmid: pMCSG7 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pLysS
References: UniProt: Q16539, mitogen-activated protein kinase

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Non-polymers , 6 types, 330 molecules

#2: Chemical ChemComp-A1BLA / (5P)-N,N-dimethyl-5-(naphthalen-1-yl)-6-(pyridin-4-yl)pyrazin-2-amine


Mass: 326.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18N4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GG5 / 4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE


Mass: 239.248 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H10FN3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 323 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.4 Å3/Da / Density % sol: 48.6 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: Protein: 20.0 mg/ml, 0.15M Sodium chloride, 0.02M Tris-HCl (pH 8.3), 1mM TCEP; Screen: 0.15M Ammomium acetate, 0.1M Bis-Tris (pH 5.5), 16% (w/v) PEG1000; Soak: 3 hrs, 5mM ligand in screen ...Details: Protein: 20.0 mg/ml, 0.15M Sodium chloride, 0.02M Tris-HCl (pH 8.3), 1mM TCEP; Screen: 0.15M Ammomium acetate, 0.1M Bis-Tris (pH 5.5), 16% (w/v) PEG1000; Soak: 3 hrs, 5mM ligand in screen solution; Cryo: 10% Glycerol in screen solution.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 10, 2011
RadiationMonochromator: C(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 1.65→30 Å / Num. obs: 47571 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 7.4 % / Biso Wilson estimate: 26 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.044 / Rpim(I) all: 0.018 / Rrim(I) all: 0.048 / Rsym value: 0.044 / Χ2: 1.005 / Net I/σ(I): 44.9
Reflection shellResolution: 1.65→1.68 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.969 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 2343 / CC1/2: 0.746 / CC star: 0.924 / Rpim(I) all: 0.381 / Rsym value: 0.969 / Χ2: 1.002 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→28.3 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.949 / SU B: 3.618 / SU ML: 0.063 / Cross valid method: THROUGHOUT / ESU R: 0.093 / ESU R Free: 0.091 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20174 2273 4.8 %RANDOM
Rwork0.17254 ---
obs0.17393 45229 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.536 Å2
Baniso -1Baniso -2Baniso -3
1-0.2 Å2-0 Å2-0 Å2
2---0.52 Å20 Å2
3---0.33 Å2
Refinement stepCycle: 1 / Resolution: 1.65→28.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2724 0 84 323 3131
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0123035
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162885
X-RAY DIFFRACTIONr_angle_refined_deg1.5241.8444133
X-RAY DIFFRACTIONr_angle_other_deg0.5191.7766641
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.0335367
X-RAY DIFFRACTIONr_dihedral_angle_2_deg4.462524
X-RAY DIFFRACTIONr_dihedral_angle_3_deg7.39110525
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.080.2449
X-RAY DIFFRACTIONr_gen_planes_refined0.0170.023603
X-RAY DIFFRACTIONr_gen_planes_other0.0130.02714
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.0851.7921428
X-RAY DIFFRACTIONr_mcbond_other2.0511.7871426
X-RAY DIFFRACTIONr_mcangle_it3.1773.1931804
X-RAY DIFFRACTIONr_mcangle_other3.1763.1941805
X-RAY DIFFRACTIONr_scbond_it3.1312.2231607
X-RAY DIFFRACTIONr_scbond_other3.132.2251608
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.8063.92329
X-RAY DIFFRACTIONr_long_range_B_refined8.09322.993622
X-RAY DIFFRACTIONr_long_range_B_other8.00921.623539
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.65→1.693 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.249 161 -
Rwork0.239 3301 -
obs--99.57 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.64690.70020.66846.9171-2.23523.8711-0.0266-0.3024-0.10270.70020.18130.5488-0.3745-0.2768-0.15480.15620.00430.06490.11470.10260.1519-16.473-0.22221.157
21.9045-1.01670.383.1754-1.77281.64490.0752-0.0455-0.10160.14660.06870.1937-0.0941-0.1298-0.14390.1018-0.0007-0.00510.01590.01090.0448-7.4665.01511.193
35.8178-1.53251.63440.5276-0.66631.43720.0686-0.63230.04020.08160.12140.1211-0.2108-0.1568-0.190.2917-0.06310.04050.20880.03240.2234-3.3660.6421.537
42.15490.74030.09792.3934-0.7031.40050.0942-0.0862-0.11260.0596-0.15460.09380.12720.08630.06040.1123-0.00420.01350.04360.03750.06810.708-3.78118.213
52.35531.0539-0.2562.7471-0.47081.44260.1038-0.18970.17710.2149-0.1084-0.0346-0.02730.08260.00460.0792-0.017-0.01490.06540.0330.064320.79510.89119.3
61.6339-0.008-0.08171.5419-0.20080.43170.0239-0.1714-0.12910.0827-0.1282-0.42710.0320.18820.10420.13790.0205-0.00270.13930.07430.139924.7291.90715.503
72.5178-1.44680.40095.7816-4.36483.62540.07760.1715-0.1297-0.3830.01840.29090.2541-0.0547-0.0960.15280.0303-0.04290.07890.01370.1192-8.4897.5812.587
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 48
2X-RAY DIFFRACTION2A49 - 96
3X-RAY DIFFRACTION3A97 - 120
4X-RAY DIFFRACTION4A121 - 167
5X-RAY DIFFRACTION5A168 - 250
6X-RAY DIFFRACTION6A251 - 324
7X-RAY DIFFRACTION7A325 - 353

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