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- PDB-3bv3: Morpholino pyrrolotriazine P38 Alpha Map Kinase inhibitor compound 2 -

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Basic information

Entry
Database: PDB / ID: 3bv3
TitleMorpholino pyrrolotriazine P38 Alpha Map Kinase inhibitor compound 2
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / KINASE / P38 MAP KINASE / Alternative splicing / ATP-binding / Cytoplasm / Nucleotide-binding / Nucleus / Phosphoprotein
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 / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / 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 / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / 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 / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / D-glucose import / Activation of the AP-1 family of transcription factors / p38MAPK cascade / ERK/MAPK targets / Regulation of MITF-M-dependent genes involved in pigmentation / fatty acid oxidation / MAP kinase kinase activity / cellular response to lipoteichoic acid / response to muramyl dipeptide / response to dietary excess / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / JUN kinase activity / 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 / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / response to insulin / 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 / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / positive regulation of protein import into nucleus / glucose metabolic process / spindle pole / chemotaxis / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / secretory granule lumen / 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 / 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
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
Chem-P39 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.59 Å
AuthorsSack, J.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38 alpha MAP kinase inhibitors.
Authors: Wrobleski, S.T. / Lin, S. / Hynes, J. / Wu, H. / Pitt, S. / Shen, D.R. / Zhang, R. / Gillooly, K.M. / Shuster, D.J. / McIntyre, K.W. / Doweyko, A.M. / Kish, K.F. / Tredup, J.A. / Duke, G.J. ...Authors: Wrobleski, S.T. / Lin, S. / Hynes, J. / Wu, H. / Pitt, S. / Shen, D.R. / Zhang, R. / Gillooly, K.M. / Shuster, D.J. / McIntyre, K.W. / Doweyko, A.M. / Kish, K.F. / Tredup, J.A. / Duke, G.J. / Sack, J.S. / McKinnon, M. / Dodd, J. / Barrish, J.C. / Schieven, G.L. / Leftheris, K.
History
DepositionJan 4, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)42,6952
Polymers42,1051
Non-polymers5901
Water1,69394
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.313, 74.939, 78.807
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 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Cytokine suppressive anti- ...Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID-binding protein / CSBP / MAX-interacting protein 2 / MAP kinase MXI2 / SAPK2A


Mass: 42105.004 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 / Cell line (production host): BL21 DE3 / Production host: Escherichia coli (E. coli)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-P39 / 5-methyl-4-[(2-methyl-5-{[(3-morpholin-4-ylphenyl)carbonyl]amino}phenyl)amino]-N-[(1S)-1-phenylethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide


Mass: 589.687 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H35N7O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 2.3 Å3/Da / Density % sol: 46.48 %
Crystal growpH: 6
Details: 1-6% (W/V) PEG-4K, 50 MM MES, 5 MM MAGNESIUM SULFATE, pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Sep 29, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.59→50 Å / Num. obs: 12467 / % possible obs: 97.8 % / Observed criterion σ(I): 0 / Redundancy: 4.4 % / Biso Wilson estimate: 62.512 Å2 / Rmerge(I) obs: 0.108 / Net I/σ(I): 17.3
Reflection shellResolution: 2.59→2.73 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.694 / Mean I/σ(I) obs: 2 / % possible all: 97.2

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Processing

Software
NameVersionClassification
BUSTER-TNT2.1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.59→24.42 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.284 647 5.19 %RANDOM
Rwork0.193 ---
obs0.1975 12461 97.82 %-
Displacement parametersBiso mean: 54.37 Å2
Baniso -1Baniso -2Baniso -3
1--20.17488146 Å20 Å20 Å2
2--13.40116975 Å20 Å2
3---6.77371171 Å2
Refinement stepCycle: LAST / Resolution: 2.59→24.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2731 0 44 94 2869
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.00628442
X-RAY DIFFRACTIONt_angle_deg0.91938472
X-RAY DIFFRACTIONt_dihedral_angle_d27.5395590
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes0.008832
X-RAY DIFFRACTIONt_gen_planes0.0114025
X-RAY DIFFRACTIONt_it1.402284420
X-RAY DIFFRACTIONt_nbd0.0361105
LS refinement shellResolution: 2.59→2.75 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2881 108 5.73 %
Rwork0.2426 1776 -
all0.2454 1884 -
obs--97.82 %

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