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- PDB-7be4: Crystal structure of MAP kinase p38 alpha in complex with inhibit... -

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Basic information

Entry
Database: PDB / ID: 7be4
TitleCrystal structure of MAP kinase p38 alpha in complex with inhibitor SR159
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / MAPK14 / kinase inhibitor / structure-guided design / structural genomics consortium / SGC
Function / homology
Function and homology information


p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / myoblast differentiation involved in skeletal muscle regeneration / Regulation of MITF-M-dependent genes involved in pigmentation / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence ...p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / myoblast differentiation involved in skeletal muscle regeneration / Regulation of MITF-M-dependent genes involved in pigmentation / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence / ADP signalling through P2Y purinoceptor 1 / Regulation of TP53 Activity through Phosphorylation / Myogenesis / VEGFA-VEGFR2 Pathway / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / positive regulation of myoblast fusion / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / D-glucose import / p38MAPK cascade / fatty acid oxidation / response to dietary excess / cellular response to lipoteichoic acid / response to muramyl dipeptide / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / 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 / positive regulation of brown fat cell differentiation / response to muscle stretch / striated muscle cell differentiation / Neutrophil degranulation / 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 / stem cell differentiation / negative regulation of canonical Wnt signaling pathway / response to insulin / bone development / cellular response to virus / positive regulation of protein import into nucleus / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / cell morphogenesis / spindle pole / osteoblast differentiation / cellular response to tumor necrosis factor / kinase activity / MAPK cascade / cellular response to lipopolysaccharide / angiogenesis / protein phosphatase binding / response to lipopolysaccharide / transcription by RNA polymerase II / protein kinase activity / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / DNA damage response / positive regulation of gene expression / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / glutamatergic synapse / positive regulation of transcription by RNA polymerase II / mitochondrion / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
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 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-TK5 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsJoerger, A.C. / Schroeder, M. / Roehm, S. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2021
Title: Development of a Selective Dual Discoidin Domain Receptor (DDR)/p38 Kinase Chemical Probe.
Authors: Rohm, S. / Berger, B.T. / Schroder, M. / Chatterjee, D. / Mathea, S. / Joerger, A.C. / Pinkas, D.M. / Bufton, J.C. / Tjaden, A. / Kovooru, L. / Kudolo, M. / Pohl, C. / Bullock, A.N. / ...Authors: Rohm, S. / Berger, B.T. / Schroder, M. / Chatterjee, D. / Mathea, S. / Joerger, A.C. / Pinkas, D.M. / Bufton, J.C. / Tjaden, A. / Kovooru, L. / Kudolo, M. / Pohl, C. / Bullock, A.N. / Muller, S. / Laufer, S. / Knapp, S.
History
DepositionDec 22, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 3, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 14, 2022Group: Database references / Category: citation / citation_author / database_2
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 / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)42,0592
Polymers41,3951
Non-polymers6641
Water1,15364
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16390 Å2
Unit cell
Length a, b, c (Å)66.460, 75.240, 78.190
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Mitogen-activated protein kinase 14 / MAPK 14 / CRK1 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha


Mass: 41395.211 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Mapk14, Crk1, Csbp1, Csbp2 / Production host: Escherichia coli (E. coli)
References: UniProt: P47811, mitogen-activated protein kinase
#2: Chemical ChemComp-TK5 / 5-azanyl-~{N}-[[4-[[(2~{S})-4-cyclohexyl-1-[[(3~{R})-1-methylsulfonylpiperidin-3-yl]amino]-1-oxidanylidene-butan-2-yl]carbamoyl]phenyl]methyl]-1-phenyl-pyrazole-4-carboxamide


Mass: 663.830 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H45N7O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 64 / 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: 2.36 Å3/Da / Density % sol: 47.91 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 20% MMW PEG smear, 0.1M MES pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 22, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.1→78.19 Å / Num. obs: 23058 / % possible obs: 98.2 % / Redundancy: 3.3 % / Biso Wilson estimate: 37.3277444709 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.062 / Net I/σ(I): 7.3
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 3333 / CC1/2: 0.747 / % possible all: 98.8

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LAR

5lar


Resolution: 2.1→50.6389 Å / SU ML: 0.294003724423 / Cross valid method: FREE R-VALUE / σ(F): 1.33416417525 / Phase error: 29.5764055922
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.267854803463 1137 4.99363169221 %
Rwork0.214513173644 21632 -
obs0.21718782692 22769 96.8110889068 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 52.3287626909 Å2
Refinement stepCycle: LAST / Resolution: 2.1→50.6389 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2580 0 47 64 2691
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008405921344942690
X-RAY DIFFRACTIONf_angle_d1.006421216813663
X-RAY DIFFRACTIONf_chiral_restr0.0612913602103418
X-RAY DIFFRACTIONf_plane_restr0.0059515979759485
X-RAY DIFFRACTIONf_dihedral_angle_d16.93824814951626
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.19560.3534806382441400.2760656933112713X-RAY DIFFRACTION98.753894081
2.1956-2.31140.5594986140681300.4033737879122440X-RAY DIFFRACTION89.2361111111
2.3114-2.45620.292186612241510.2442436277222742X-RAY DIFFRACTION99.1772368872
2.4562-2.64580.3108010155491270.253458933552738X-RAY DIFFRACTION98.6910093007
2.6458-2.9120.2783952607031510.2290421094932676X-RAY DIFFRACTION96.881425634
2.912-3.33330.2728430227951580.2267475355472727X-RAY DIFFRACTION98.2294858699
3.3333-4.19940.236445232791370.1804469241562742X-RAY DIFFRACTION96.936026936
4.1994-50.60.2155168443261430.182261433792854X-RAY DIFFRACTION96.5528350515
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)
13.50149282010.477238843456-0.1380552762923.02294501356-0.3770324542023.315268437720.0313624586250.5319663681780.34325360722-0.4688604312020.1166024645560.8809595517680.00849365869525-0.706847974566-0.1211841828670.3560062281420.0184729828337-0.09465591183880.3985265974120.04394089498910.4524581307-9.63311183066-2.15432812879-16.9883342879
26.355073586860.274896231814-1.291883267363.108335580531.704351756294.990335713830.0195097323170.2767862631560.0470244238151-0.187147145106-0.144111569641-0.0112764133638-0.015988299341-0.01406103852170.1495848047710.2123373057190.0123592100971-0.006315587258030.2085268167080.03920031626520.1964664140212.6248839276-1.47180875355-18.2436227367
33.929866536980.515091471589-0.6690639528421.86362333213-0.2028113099271.6622028430.0963251819137-0.160106289796-0.0166367189394-0.0720069284155-0.15964799011-0.236230234146-0.04445022629620.3204193534020.07737731902960.29754957923-0.0158918741089-0.04370925271550.2523442158020.05307075619930.15443658116117.0205849749-6.16465033262-13.7639137114
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 4 through 123 )
2X-RAY DIFFRACTION2chain 'A' and (resid 124 through 218 )
3X-RAY DIFFRACTION3chain 'A' and (resid 219 through 352 )

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