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- PDB-3mvl: P38 Alpha Map Kinase complexed with pyrrolotriazine inhibitor 7K -

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Basic information

Entry
Database: PDB / ID: 3mvl
TitleP38 Alpha Map Kinase complexed with pyrrolotriazine inhibitor 7K
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / KINASE / P38 MAP 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 / 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 ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / 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 myoblast fusion / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / D-glucose import / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / p38MAPK cascade / 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 / MAP kinase activity / RHO GTPases Activate NADPH Oxidases / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / mitogen-activated protein kinase / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / 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 / positive regulation of D-glucose import / stem cell differentiation / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / negative regulation of inflammatory response to antigenic stimulus / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / placenta development / NOD1/2 Signaling Pathway / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / glucose metabolic process / ADP signalling through P2Y purinoceptor 1 / chemotaxis / positive regulation of reactive oxygen species metabolic process / cellular senescence / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / 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 / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / apoptotic process / 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 ...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-38P / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsSack, J.S.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-Methylphenylamino)-5-Methyl-Npropylpyrrolo[1,2-F][1,2,4] Triazine-6-Carboxamide (Bms-582949), a Clinical P38 Map Kinase Inhibitor for the Treatment ...Title: Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-Methylphenylamino)-5-Methyl-Npropylpyrrolo[1,2-F][1,2,4] Triazine-6-Carboxamide (Bms-582949), a Clinical P38 Map Kinase Inhibitor for the Treatment of Inflammatory Diseases
Authors: Liu, C. / Lin, J. / Wrobleski, S.T. / Lin, S. / Hynes, J. / Wu, H. / Dyckman, A.J. / Li, T. / Wityak, J. / Gillooly, K.M. / Pitt, S. / Shen, D.R. / Zhang, R.F. / McIntyre, K.W. / Salter-Cid, ...Authors: Liu, C. / Lin, J. / Wrobleski, S.T. / Lin, S. / Hynes, J. / Wu, H. / Dyckman, A.J. / Li, T. / Wityak, J. / Gillooly, K.M. / Pitt, S. / Shen, D.R. / Zhang, R.F. / McIntyre, K.W. / Salter-Cid, L. / Shuster, D.J. / Zhang, H. / Marathe, P.H. / Doweyko, A.M. / Sack, J.S. / Kiefer, S.E. / Kish, K.F. / Newitt, J.A. / McKinnon, M. / Dodd, J.H. / Barrish, J.C. / Schieven, G.L. / Leftheris, K.
History
DepositionMay 4, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 13, 2010Provider: 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
B: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,0234
Polymers84,2102
Non-polymers8132
Water2,252125
1
A: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5112
Polymers42,1051
Non-polymers4061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5112
Polymers42,1051
Non-polymers4061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.540, 71.680, 72.820
Angle α, β, γ (deg.)90.00, 90.01, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Mitogen-activated protein kinase 14 / MAP kinase 14 / MAPK 14 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / ...MAP kinase 14 / MAPK 14 / 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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSBP, CSBP1, CSBP2, CSPB1, MAPK14, MXI2 / Cell line (production host): BL21 DE3 / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-38P / 4-{[5-(cyclopropylcarbamoyl)-2-methylphenyl]amino}-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide


Mass: 406.481 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H26N6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / 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: 2.09 Å3/Da / Density % sol: 41.24 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: May 28, 2002 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.8→40.75 Å / Num. obs: 17200 / % possible obs: 99.5 % / Observed criterion σ(I): 0 / Redundancy: 4.2 % / Biso Wilson estimate: 49.51 Å2 / Rmerge(I) obs: 0.041 / Net I/σ(I): 31.5
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.124 / Mean I/σ(I) obs: 12 / % possible all: 97.2

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Processing

Software
NameVersionClassification
BUSTER2.9.4refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→33.77 Å / Cor.coef. Fo:Fc: 0.8028 / Cor.coef. Fo:Fc free: 0.6036 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.3349 871 5.06 %RANDOM
Rwork0.2272 ---
obs0.2326 17198 99.42 %-
Displacement parametersBiso mean: 30.17 Å2
Baniso -1Baniso -2Baniso -3
1-4.9465 Å20 Å20.9446 Å2
2--5.0893 Å20 Å2
3----10.0358 Å2
Refine analyzeLuzzati coordinate error obs: 0.399 Å
Refinement stepCycle: LAST / Resolution: 2.8→33.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5482 0 60 125 5667
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.0156762
X-RAY DIFFRACTIONt_angle_deg1.2577082
X-RAY DIFFRACTIONt_dihedral_angle_d19582
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes1382
X-RAY DIFFRACTIONt_gen_planes8085
X-RAY DIFFRACTIONt_it567620
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.64
X-RAY DIFFRACTIONt_other_torsion24.42
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion7285
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact65704
LS refinement shellResolution: 2.8→2.97 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.3508 140 5.22 %
Rwork0.2315 2543 -
all0.2382 2683 -
obs--99.42 %

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