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- PDB-5xyy: The structure of p38 alpha in complex with a triazol inhibitor -

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Basic information

Entry
Database: PDB / ID: 5xyy
TitleThe structure of p38 alpha in complex with a triazol inhibitor
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / p38 MAP kinase / Transferase / Transferase-Transferase inhibitor complex
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 / cartilage condensation ...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 / cartilage condensation / DSCAM interactions / 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 / regulation of cytokine production involved in inflammatory response / ERK/MAPK targets / 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 / cellular response to vascular endothelial growth factor stimulus / mitogen-activated protein kinase / signal transduction in response to DNA damage / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / positive regulation of cardiac muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / negative regulation of inflammatory response to antigenic stimulus / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / positive regulation of brown fat cell differentiation / 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 / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / placenta development / 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 / chemotaxis / positive regulation of reactive oxygen species metabolic process / cellular senescence / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / peptidyl-serine phosphorylation / protein phosphatase binding / angiogenesis / secretory granule lumen / 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 / 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-P0F / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsWang, Y.L. / Sun, Y.Z. / Cao, R. / Liu, D. / Li, L. / Qi, X.B. / Huang, N.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J. Med. Chem. / Year: 2017
Title: In Silico Identification of a Novel Hinge-Binding Scaffold for Kinase Inhibitor Discovery.
Authors: Wang, Y. / Sun, Y. / Cao, R. / Liu, D. / Xie, Y. / Li, L. / Qi, X. / Huang, N.
History
DepositionJul 11, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 17, 2018Provider: repository / Type: Initial release
Revision 1.1May 23, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.0Apr 10, 2024Group: Advisory / Atomic model ...Advisory / Atomic model / Author supporting evidence / Data collection / Derived calculations / Non-polymer description / Other / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / atom_sites / chem_comp / chem_comp_atom / chem_comp_bond / diffrn / entity / entity_src_gen / pdbx_audit_support / pdbx_contact_author / pdbx_entity_instance_feature / pdbx_entity_nonpoly / pdbx_entry_details / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_refine_tls / pdbx_refine_tls_group / pdbx_struct_assembly_gen / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / pdbx_validate_peptide_omega / pdbx_validate_planes / pdbx_validate_rmsd_angle / pdbx_validate_rmsd_bond / pdbx_validate_torsion / refine / refine_hist / refine_ls_restr / refine_ls_shell / reflns / reflns_shell / software / struct_asym / struct_conf / struct_sheet_range / struct_site / struct_site_gen
Item: _atom_sites.fract_transf_matrix[2][1] / _atom_sites.fract_transf_matrix[3][2] ..._atom_sites.fract_transf_matrix[2][1] / _atom_sites.fract_transf_matrix[3][2] / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _diffrn.pdbx_serial_crystal_experiment / _entity_src_gen.gene_src_common_name / _pdbx_contact_author.fax / _pdbx_contact_author.id / _pdbx_contact_author.identifier_ORCID / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.auth_seq_num / _pdbx_poly_seq_scheme.pdb_mon_id / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_sheet_hbond.range_1_auth_comp_id / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_1_label_comp_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_comp_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_label_comp_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _refine.B_iso_mean / _refine.aniso_B[1][1] / _refine.aniso_B[1][2] / _refine.aniso_B[1][3] / _refine.aniso_B[2][2] / _refine.aniso_B[2][3] / _refine.aniso_B[3][3] / _refine.correlation_coeff_Fo_to_Fc / _refine.correlation_coeff_Fo_to_Fc_free / _refine.details / _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.ls_R_factor_obs / _refine.ls_d_res_low / _refine.ls_number_reflns_obs / _refine.ls_percent_reflns_R_free / _refine.ls_percent_reflns_obs / _refine.overall_SU_B / _refine.overall_SU_ML / _refine.pdbx_ls_sigma_F / _refine.pdbx_overall_ESU_R / _refine.pdbx_overall_ESU_R_Free / _refine.pdbx_overall_phase_error / _refine.pdbx_solvent_ion_probe_radii / _refine.pdbx_solvent_shrinkage_radii / _refine.pdbx_solvent_vdw_probe_radii / _refine.pdbx_stereochemistry_target_values / _refine.solvent_model_details / _refine_hist.cycle_id / _refine_hist.d_res_low / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_protein / _refine_ls_shell.R_factor_R_free / _refine_ls_shell.R_factor_R_work / _refine_ls_shell.d_res_low / _refine_ls_shell.number_reflns_R_free / _refine_ls_shell.number_reflns_R_work / _refine_ls_shell.number_reflns_obs / _refine_ls_shell.pdbx_total_number_of_bins_used / _refine_ls_shell.percent_reflns_obs / _reflns.pdbx_Rmerge_I_obs / _reflns.pdbx_Rrim_I_all / _software.name / _software.version / _struct_sheet_range.end_auth_comp_id / _struct_sheet_range.end_auth_seq_id / _struct_sheet_range.end_label_comp_id / _struct_sheet_range.end_label_seq_id
Description: Model completeness / Provider: author / Type: Coordinate replacement

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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)43,8332
Polymers43,5151
Non-polymers3191
Water5,765320
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.940, 86.600, 124.680
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 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSBP / MAP kinase MXI2 / ...MAPK 14 / Cytokine suppressive anti-inflammatory drug-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: 43514.543 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 / Production host: Escherichia coli (E. coli)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-P0F / 3-(5-{[(2-chloro-6-fluorophenyl)methyl]amino}-4H-1,2,4-triazol-3-yl)phenol


Mass: 318.733 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H12ClFN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 320 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.02 Å3/Da / Density % sol: 59.29 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: Sodium citrate, Ammonium sulfate, HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.9793 Å
DetectorType: RIGAKU / Detector: CCD / Date: Jul 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 1.7→33.6 Å / Num. obs: 54433 / % possible obs: 99.9 % / Redundancy: 7.3 % / Rmerge(I) obs: 0.08 / Rrim(I) all: 0.086 / Net I/σ(I): 15.6
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsRpim(I) allRrim(I) allDiffraction-ID% possible all
5.38-33.60.03318730.0130.036198.3
1.7-1.790.38378470.1530.4131100

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Processing

Software
NameVersionClassification
PHENIX1.19.2refinement
iMOSFLMdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1OUY

1ouy


Resolution: 1.7→31.18 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 18.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2007 2765 5.09 %RANDOM
Rwork0.1786 ---
obs0.1797 54364 99.87 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.7→31.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2771 0 22 322 3115
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0192875
X-RAY DIFFRACTIONf_angle_d1.3213909
X-RAY DIFFRACTIONf_dihedral_angle_d5.613381
X-RAY DIFFRACTIONf_chiral_restr0.083438
X-RAY DIFFRACTIONf_plane_restr0.012500
LS refinement shellResolution: 1.7→1.73 Å
RfactorNum. reflection% reflection
Rfree0.2664 130 -
Rwork0.234 --
obs-2582 100 %
Refinement TLS params.Method: refined / Origin x: 1.3336 Å / Origin y: -25.8833 Å / Origin z: -21.3101 Å
111213212223313233
T0.1157 Å2-0.0199 Å2-0.0233 Å2-0.0971 Å2-0.012 Å2--0.0995 Å2
L0.5981 °2-0.2438 °2-0.3557 °2-0.3153 °20.0375 °2--0.4805 °2
S-0.0278 Å °-0.0123 Å °-0.0376 Å °-0.0008 Å °0.0321 Å °-0.0059 Å °0.0198 Å °0.0233 Å °-0.0068 Å °
Refinement TLS groupSelection details: all

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