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

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Basic information

Entry
Database: PDB / ID: 5bve
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 / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / 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 / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / ERKs are inactivated / cytosine metabolic process / Signaling by MAP2K mutants / Signaling by NODAL / response to epidermal growth factor / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / Regulation of the apoptosome activity / positive regulation of macrophage proliferation / regulation of cellular pH / outer ear morphogenesis / Signaling by LTK in cancer / regulation of Golgi inheritance / labyrinthine layer blood vessel development / ERBB signaling pathway / 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 / ERBB2-ERBB3 signaling pathway / MAPK1 (ERK2) activation / positive regulation of macrophage chemotaxis / Activation of the AP-1 family of transcription factors / regulation of cytoskeleton organization / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / response to exogenous dsRNA / face development / positive regulation of telomere maintenance / lung morphogenesis / Recycling pathway of L1 / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / Advanced glycosylation endproduct receptor signaling / thyroid gland development / steroid hormone receptor signaling pathway / negative regulation of cell differentiation / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / JUN kinase activity / mitogen-activated protein kinase / Signal attenuation / progesterone receptor signaling pathway / Estrogen-stimulated signaling through PRKCZ / phosphatase binding / Schwann cell development / Growth hormone receptor signaling / positive regulation of peptidyl-threonine phosphorylation / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / NPAS4 regulates expression of target genes / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / Transcriptional and post-translational regulation of MITF-M expression and activity / NCAM signaling for neurite out-growth / ERK1 and ERK2 cascade / cellular response to amino acid starvation / insulin-like growth factor receptor signaling pathway / lipopolysaccharide-mediated signaling pathway / ESR-mediated signaling / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / peptidyl-threonine phosphorylation / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / response to nicotine / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR1 signaling / positive regulation of cholesterol biosynthetic process / long-term synaptic potentiation / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / regulation of protein stability / Oncogene Induced Senescence / caveola / 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. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / 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 / 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-4VG / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 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)42,3346
Polymers41,4681
Non-polymers8665
Water4,756264
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.242, 70.672, 120.307
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-4VG / 2-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-8-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepin-1-one


Mass: 481.975 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H28ClN5O3
#3: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 264 / 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: 2.27 Å3/Da / Density % sol: 45.76 %
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: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS / Detector: IMAGE PLATE / Date: May 29, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→70.67 Å / Num. obs: 26269 / % possible obs: 99.9 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.064 / Net I/σ(I): 16.5

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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: 2→41.523 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2198 1332 5.08 %Random selection
Rwork0.1725 ---
obs0.1748 26200 99.81 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2→41.523 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2698 0 54 264 3016
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082827
X-RAY DIFFRACTIONf_angle_d1.0753832
X-RAY DIFFRACTIONf_dihedral_angle_d14.8061065
X-RAY DIFFRACTIONf_chiral_restr0.044414
X-RAY DIFFRACTIONf_plane_restr0.006508
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.07150.30941280.24762423X-RAY DIFFRACTION100
2.0715-2.15450.28241250.21592450X-RAY DIFFRACTION100
2.1545-2.25250.26921410.20232460X-RAY DIFFRACTION100
2.2525-2.37130.27291240.20012441X-RAY DIFFRACTION100
2.3713-2.51980.211430.18822465X-RAY DIFFRACTION100
2.5198-2.71430.24011370.18252456X-RAY DIFFRACTION100
2.7143-2.98740.23961400.17582481X-RAY DIFFRACTION100
2.9874-3.41950.22921400.16552482X-RAY DIFFRACTION100
3.4195-4.30750.16971280.14352532X-RAY DIFFRACTION100
4.3075-41.53220.1921260.16072678X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 6.8458 Å / Origin y: 2.934 Å / Origin z: 20.3909 Å
111213212223313233
T0.0892 Å20.0038 Å2-0.001 Å2-0.0796 Å2-0.0019 Å2--0.1029 Å2
L0.289 °2-0.0059 °2-0.2185 °2-0.1 °20.325 °2--1.1388 °2
S0.0124 Å °0.039 Å °-0.0285 Å °0.0143 Å °-0.0157 Å °-0.0342 Å °-0.0262 Å °-0.0666 Å °-0 Å °
Refinement TLS groupSelection details: all

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