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- PDB-1w7h: p38 Kinase crystal structure in complex with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 1w7h
Titlep38 Kinase crystal structure in complex with small molecule inhibitor
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 14
KeywordsTRANSFERASE / P38 / KINASE / INHIBITOR COMPLEX / PHOSPHORYLATION / SERINE/THREONINE-PROTEIN KINASE
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
3-(BENZYLOXY)PYRIDIN-2-AMINE / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.214 Å
AuthorsJhoti, H. / Gill, A. / Cleasby, A. / Devine, L.
CitationJournal: J.Med.Chem. / Year: 2005
Title: Fragment-Based Lead Discovery Using X-Ray Crystallography
Authors: Hartshorn, M.J. / Murray, C.W. / Cleasby, A. / Frederickson, M. / Tickle, I.J. / Jhoti, H.
History
DepositionSep 2, 2004Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 8, 2005Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jul 5, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Dec 13, 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

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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)41,5432
Polymers41,3431
Non-polymers2001
Water8,431468
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)45.771, 87.101, 126.337
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 / P38 MAP KINASE / MITOGEN-ACTIVATED PROTEIN KINASE P38 ALPHA / MAP KINASE P38ALPHA / CYTOKINE ...P38 MAP KINASE / MITOGEN-ACTIVATED PROTEIN KINASE P38 ALPHA / MAP KINASE P38ALPHA / CYTOKINE SUPPRESSIVE ANTI-INFLAMMATORY DRUG BINDING PROTEIN CSAID BINDING PROTEIN / CSBP / MAX-INTERACTING PROTEIN 2 MAP KINASE MXI2 / SAPK2A


Mass: 41343.195 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q16539, EC: 2.7.1.37
#2: Chemical ChemComp-3IP / 3-(BENZYLOXY)PYRIDIN-2-AMINE


Mass: 200.236 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H12N2O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 468 / 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: 3.05 Å3/Da / Density % sol: 59.61 %
Crystal growpH: 7 / Details: pH 7.00

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.54
DetectorType: MSC / Detector: CCD / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.2→19.66 Å / Num. obs: 25916 / % possible obs: 94.4 % / Observed criterion σ(I): 2 / Redundancy: 2.5 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 11.1

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Processing

Software
NameClassification
CNSrefinement
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1P38

1p38
PDB Unreleased entry


Resolution: 2.214→19.663 Å / Data cutoff high absF: 10000 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: DIFFERENCE DENSITY IN THE ACTIVE SITE SUGGESTS BINDING OF EITHER A SECOND INHIBITOR MOLECULE AT LOWER OCCUPANCY OR A BUFFER MOLECULE. THIS IS AMBIGUOUS AND HAS BEEN MODELLED AS WATER MOLECULES
RfactorNum. reflection% reflectionSelection details
Rfree0.2329 1254 4.8 %RANDOM
Rwork0.1828 ---
obs0.1828 24534 94.8 %-
Solvent computationBsol: 54.4176 Å2 / ksol: 0.371603 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.432 Å20 Å20 Å2
2--1.616 Å20 Å2
3----1.184 Å2
Refinement stepCycle: LAST / Resolution: 2.214→19.663 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2834 0 15 468 3317
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.005207
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_deg0.83719
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
X-RAY DIFFRACTION4LIG_CNX.PARLIG_CNX.TOP

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