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- PDB-3zs5: Structural basis for kinase selectivity of three clinical p38alph... -

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Basic information

Entry
Database: PDB / ID: 3zs5
TitleStructural basis for kinase selectivity of three clinical p38alpha inhibitors
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 14MAPK14
KeywordsTRANSFERASE / TAK-715 / SCIO-469 / VX-745 / SB-203580
Function / homology
Function and homology information


positive regulation of cyclase activity / stress-activated protein kinase signaling cascade / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / CD163 mediating an anti-inflammatory response / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / DSCAM interactions ...positive regulation of cyclase activity / stress-activated protein kinase signaling cascade / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / CD163 mediating an anti-inflammatory response / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / DSCAM interactions / cartilage condensation / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / positive regulation of muscle cell differentiation / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / glucose import / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / MAP kinase kinase activity / response to dietary excess / response to muramyl dipeptide / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / positive regulation of myoblast differentiation / signal transduction in response to DNA damage / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / positive regulation of cardiac muscle cell proliferation / negative regulation of inflammatory response to antigenic stimulus / 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 / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / placenta development / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / platelet activation / cellular response to virus / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / cellular senescence / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / protein phosphatase binding / secretory granule lumen / Oxidative Stress Induced Senescence / angiogenesis / Regulation of TP53 Activity through Phosphorylation / cellular response to lipopolysaccharide / 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 / glutamatergic synapse / apoptotic process / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / 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. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-SB2 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsAzevedo, R. / van Zeeland, M. / Raaijmakers, H.C.A. / Kazemier, B. / Oubrie, A.
CitationJournal: Acta Crystallogr. D Biol. Crystallogr. / Year: 2012
Title: X-ray structure of p38 alpha bound to TAK-715: comparison with three classic inhibitors.
Authors: Azevedo, R. / van Zeeland, M. / Raaijmakers, H. / Kazemier, B. / de Vlieg, J. / Oubrie, A.
History
DepositionJun 23, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 4, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 25, 2012Group: Database references
Revision 1.2Aug 15, 2012Group: Database references
Revision 1.3Feb 7, 2018Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _audit_author.name / _citation.country ..._audit_author.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_last / _citation.title / _citation_author.name
Revision 1.4May 8, 2019Group: Data collection / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow
Item: _exptl_crystal_grow.method
Revision 1.5Jul 29, 2020Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_database_status / pdbx_entity_nonpoly / struct_site / struct_site_gen
Item: _chem_comp.mon_nstd_flag / _chem_comp.name ..._chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.6May 8, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: MITOGEN-ACTIVATED PROTEIN KINASE 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6437
Polymers41,4941
Non-polymers1,1486
Water5,242291
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.492, 70.036, 75.010
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein MITOGEN-ACTIVATED PROTEIN KINASE 14 / MAPK14 / P38A / MAP KINASE 14 / MAPK 14 / CYTOKINE SUPPRESSIVE ANTI-INFLAMMATORY DRUG-BINDING PROTEIN / ...P38A / 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 / SAPK2A


Mass: 41494.277 Da / Num. of mol.: 1 / Fragment: RESIDUES 2-360
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PMAL-C2X LIKE / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): ROSETTA
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-SB2 / 4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINE


Mass: 377.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16FN3OS
#3: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside / Octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 291 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL -PYRIDINE

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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: 2.33 Å3/Da / Density % sol: 47 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / pH: 6.5
Details: HANGING DROP, ROOM TEMP, 20 MM HEPES PH7.1, 50 MM NACL, 10 MM DTT, 5% GLYCEROL, 0.1 G/L METHIONINE, 28% PEG 4K,0.1 M MES PH=6.5, 50 MM N-OCTYL-BETAGLUCOSIDE. CRYOPROTECTANT 28% PEG 4K, 0.1M ...Details: HANGING DROP, ROOM TEMP, 20 MM HEPES PH7.1, 50 MM NACL, 10 MM DTT, 5% GLYCEROL, 0.1 G/L METHIONINE, 28% PEG 4K,0.1 M MES PH=6.5, 50 MM N-OCTYL-BETAGLUCOSIDE. CRYOPROTECTANT 28% PEG 4K, 0.1M MES PH5.9, 50 MM N-OCTYL-BETAGLUCOSIDE, 20% ETHYLENE GLYCOL.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.933
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Sep 28, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 1.6→40.7 Å / Num. obs: 44440 / % possible obs: 93.8 % / Observed criterion σ(I): 0 / Redundancy: 6.9 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 8
Reflection shellResolution: 1.6→1.69 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.88 / Mean I/σ(I) obs: 2.2 / % possible all: 75.3

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Processing

Software
NameVersionClassification
REFMAC5.5.0102refinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→51.16 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.947 / SU B: 3.941 / SU ML: 0.062 / Cross valid method: THROUGHOUT / ESU R: 0.101 / ESU R Free: 0.099 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. LYS 53 SHOWS SOME DISORDER AROUND NZETA AND FORMS A SALTBRIDGE TO GLU71. TWO WATERS NEXT TO LYS53 ARE PROBABLY ONLY PARTLY OCCUPIED. THERE ...Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. LYS 53 SHOWS SOME DISORDER AROUND NZETA AND FORMS A SALTBRIDGE TO GLU71. TWO WATERS NEXT TO LYS53 ARE PROBABLY ONLY PARTLY OCCUPIED. THERE IS AN ADDITIONAL HYDROPHOBIC LIGAND IN THE ATP POCKET. I'VE PUT A B-OCTYLGLUCOSIDE INSIDE THOUGH THE GLUCOSIDE PART ISN'T VERY CLEAR. IT COULD BE A SIDE CHAIN FROM THE ACTIVATION LOOP BUT IT DOESN'T MAKE H-BONDS. METHIONINE WOULD BE A BIT SHORT.
RfactorNum. reflection% reflectionSelection details
Rfree0.21527 2232 5 %RANDOM
Rwork0.18433 ---
obs0.18586 42175 93.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.088 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å20 Å20 Å2
2---0.14 Å20 Å2
3----0.04 Å2
Refinement stepCycle: LAST / Resolution: 1.6→51.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2740 0 75 291 3106
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222977
X-RAY DIFFRACTIONr_bond_other_d0.0020.022053
X-RAY DIFFRACTIONr_angle_refined_deg1.2711.9824045
X-RAY DIFFRACTIONr_angle_other_deg0.84435008
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3665364
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.47223.741139
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.87915517
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2751521
X-RAY DIFFRACTIONr_chiral_restr0.0780.2449
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213254
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02605
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_it1.45821748
X-RAY DIFFRACTIONr_mcbond_other0.3632692
X-RAY DIFFRACTIONr_mcangle_it2.36732849
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.76821229
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.77631186
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.6→1.642 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.338 102 -
Rwork0.304 2201 -
obs--66.95 %
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)
11.5596-0.3054-0.05990.61890.02870.39750.0348-0.01290.1591-0.0177-0.0144-0.0671-0.06020.0378-0.02050.0925-0.01120.00070.02360.00750.031212.1531.86917.067
23.2531-3.6273-1.649113.6301-0.90715.38810.2371-0.33350.41830.89750.01340.1077-0.2553-0.3762-0.25060.1955-0.09330.08890.2052-0.02560.1978-13.17230.18136.952
31.8692-0.00411.30812.1985-1.0154.61650.0736-0.1107-0.1683-0.04260.03970.03380.14930.005-0.11330.0667-0.0012-0.02380.01210.01710.043625.82917.41325.605
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A5 - 166
2X-RAY DIFFRACTION1A185 - 240
3X-RAY DIFFRACTION1A266 - 321
4X-RAY DIFFRACTION1A1000
5X-RAY DIFFRACTION2A241 - 265
6X-RAY DIFFRACTION3A322 - 352

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