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- PDB-5bvd: Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase -

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Basic information

Entry
Database: PDB / ID: 5bvd
TitleTetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / Inhibitor / Kinase / TRANSFERASE-TRANSFERASE Inhibitor complex
Function / homology
Function and homology information


phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / ERKs are inactivated / cytosine metabolic process ...phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / ERKs are inactivated / cytosine metabolic process / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / Regulation of the apoptosome activity / outer ear morphogenesis / regulation of cellular pH / regulation of Golgi inheritance / ERBB signaling pathway / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / positive regulation of macrophage chemotaxis / lung morphogenesis / ERBB2-ERBB3 signaling pathway / response to exogenous dsRNA / regulation of cytoskeleton organization / Activation of the AP-1 family of transcription factors / face development / ERK/MAPK targets / progesterone receptor signaling pathway / androgen receptor signaling pathway / RUNX2 regulates osteoblast differentiation / pseudopodium / Recycling pathway of L1 / MAPK1 (ERK2) activation / negative regulation of cell differentiation / Bergmann glial cell differentiation / positive regulation of telomere capping / thyroid gland development / Advanced glycosylation endproduct receptor signaling / steroid hormone receptor signaling pathway / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate NADPH Oxidases / Regulation of HSF1-mediated heat shock response / MAP kinase activity / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / mitogen-activated protein kinase / phosphatase binding / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Nuclear events stimulated by ALK signaling in cancer / Schwann cell development / Growth hormone receptor signaling / stress-activated MAPK cascade / lipopolysaccharide-mediated signaling pathway / : / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / NPAS4 regulates expression of target genes / ERK1 and ERK2 cascade / cellular response to amino acid starvation / myelination / NCAM signaling for neurite out-growth / phosphotyrosine residue binding / RNA polymerase II CTD heptapeptide repeat kinase activity / ESR-mediated signaling / insulin-like growth factor receptor signaling pathway / thymus development / positive regulation of peptidyl-threonine phosphorylation / Regulation of PTEN gene transcription / Signal transduction by L1 / caveola / long-term synaptic potentiation / Negative regulation of FGFR3 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / FCERI mediated MAPK activation / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / peptidyl-threonine phosphorylation / B cell receptor signaling pathway / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / response to nicotine / MAP2K and MAPK activation / regulation of protein stability / Oncogene Induced Senescence / mitotic spindle / Regulation of actin dynamics for phagocytic cup formation
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain ...Mitogen-activated protein (MAP) kinase, ERK1/2 / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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-4VF / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsMa, X. / Steven, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase.
Authors: Bagdanoff, J.T. / Jain, R. / Han, W. / Zhu, S. / Madiera, A.M. / Lee, P.S. / Ma, X. / Poon, D.
History
DepositionJun 5, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 9, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4167
Polymers41,4681
Non-polymers9486
Water5,188288
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.271, 71.282, 120.451
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 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK ...MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK / Mitogen-activated protein kinase 2 / MAPK 2


Mass: 41467.625 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK1, ERK2, PRKM1, PRKM2 / Production host: Escherichia coli (E. coli)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-4VF / 2-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-7-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one


Mass: 467.948 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26ClN5O3
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 288 / 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: 2.29 Å3/Da / Density % sol: 46.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 20mM Mg Sulfate, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 20, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→71.28 Å / Num. obs: 30901 / % possible obs: 100 % / Redundancy: 6 % / Rmerge(I) obs: 0.069 / Net I/σ(I): 19.1

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
PROCESSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ERK

1erk
PDB Unreleased entry


Resolution: 1.9→61.345 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.79 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2068 1550 5.03 %Random selection
Rwork0.1702 ---
obs0.172 30837 99.94 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.9→61.345 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2698 0 58 288 3044
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082821
X-RAY DIFFRACTIONf_angle_d1.0583824
X-RAY DIFFRACTIONf_dihedral_angle_d14.411058
X-RAY DIFFRACTIONf_chiral_restr0.045413
X-RAY DIFFRACTIONf_plane_restr0.005506
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.96140.24951340.2072618X-RAY DIFFRACTION100
1.9614-2.03150.24571390.19862622X-RAY DIFFRACTION100
2.0315-2.11280.20521470.17732621X-RAY DIFFRACTION100
2.1128-2.2090.20721420.172619X-RAY DIFFRACTION100
2.209-2.32540.23631430.17852633X-RAY DIFFRACTION100
2.3254-2.47110.2631180.17352664X-RAY DIFFRACTION100
2.4711-2.66190.2081320.17612631X-RAY DIFFRACTION100
2.6619-2.92980.19651400.17912675X-RAY DIFFRACTION100
2.9298-3.35370.20011380.17342670X-RAY DIFFRACTION100
3.3537-4.22520.19251520.14762700X-RAY DIFFRACTION100
4.2252-61.37680.19361650.16782834X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 6.9024 Å / Origin y: 2.963 Å / Origin z: 20.1529 Å
111213212223313233
T0.0753 Å20.0059 Å20.0025 Å2-0.0669 Å2-0.0104 Å2--0.089 Å2
L0.2971 °20.0055 °2-0.1399 °2-0.118 °20.2285 °2--0.9244 °2
S-0.0026 Å °0.0444 Å °-0.0246 Å °0.0178 Å °-0.0239 Å °-0.0112 Å °-0.02 Å °-0.0651 Å °-0 Å °
Refinement TLS groupSelection details: all

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