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- PDB-5ax3: Crystal structure of ERK2 complexed with allosteric and ATP-compe... -

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Basic information

Entry
Database: PDB / ID: 5ax3
TitleCrystal structure of ERK2 complexed with allosteric and ATP-competitive inhibitors.
Components
  • Mitogen-activated protein kinase 1
  • allosteric and ATP-competitive inhibitor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / ternary complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


PTK6 Activates STAT3 / RNA sequestering activity / eye photoreceptor cell differentiation / radial glial cell differentiation / negative regulation of primary miRNA processing / retinal rod cell differentiation / leptin-mediated signaling pathway / negative regulation of hydrogen peroxide biosynthetic process / T-helper 17 type immune response / Signalling to STAT3 ...PTK6 Activates STAT3 / RNA sequestering activity / eye photoreceptor cell differentiation / radial glial cell differentiation / negative regulation of primary miRNA processing / retinal rod cell differentiation / leptin-mediated signaling pathway / negative regulation of hydrogen peroxide biosynthetic process / T-helper 17 type immune response / Signalling to STAT3 / negative regulation of neuron migration / POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation / positive regulation of extracellular matrix disassembly / negative regulation of inflammatory response to wounding / primary miRNA binding / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / cellular response to interleukin-17 / T-helper 17 cell lineage commitment / sexual reproduction / response to leptin / regulation of feeding behavior / Interleukin-9 signaling / Interleukin-21 signaling / Transcriptional regulation of pluripotent stem cells / interleukin-9-mediated signaling pathway / MET activates STAT3 / nuclear glucocorticoid receptor binding / interleukin-10-mediated signaling pathway / regulation of cellular response to hypoxia / phospho-PLA2 pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / interleukin-2-mediated signaling pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / Suppression of apoptosis / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cellular response to leptin stimulus / interleukin-15-mediated signaling pathway / cardiac neural crest cell development involved in heart development / interleukin-23-mediated signaling pathway / caveolin-mediated endocytosis / cytosine metabolic process / postsynapse to nucleus signaling pathway / Signaling by MAP2K mutants / Signaling by NODAL / Interleukin-23 signaling / response to epidermal growth factor / ERKs are inactivated / negative regulation of stem cell differentiation / astrocyte differentiation / RSK activation / Signaling by cytosolic FGFR1 fusion mutants / STAT3 nuclear events downstream of ALK signaling / Interleukin-15 signaling / Interleukin-37 signaling / Golgi Cisternae Pericentriolar Stack Reorganization / Signaling by Leptin / regulation of mitochondrial membrane permeability / positive regulation of cytokine production involved in inflammatory response / Regulation of the apoptosome activity / Interleukin-27 signaling / positive regulation of macrophage proliferation / Interleukin-35 Signalling / phosphorylation / cell surface receptor signaling pathway via STAT / negative regulation of glycolytic process / regulation of cellular pH / outer ear morphogenesis / Signaling by LTK in cancer / regulation of Golgi inheritance / positive regulation of vascular endothelial cell proliferation / positive regulation of peptidyl-threonine phosphorylation / ERBB signaling pathway / eating behavior / growth hormone receptor 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 / Signaling by ALK / Interleukin-20 family signaling / IFNG signaling activates MAPKs / regulation of stress-activated MAPK cascade / Interleukin-6 signaling / Frs2-mediated activation / temperature homeostasis / interleukin-6-mediated signaling pathway / positive regulation of Notch signaling pathway / lncRNA binding / ERBB2-ERBB3 signaling pathway / 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 / pseudopodium
Similarity search - Function
STAT3, SH2 domain / STAT transcription factor, DNA-binding, N-terminal / STAT transcription factor, protein interaction / STAT transcription factor, all-alpha domain / STAT transcription factor, DNA-binding / : / STAT transcription factor, coiled-coil domain / STAT protein, DNA binding domain / STAT protein, protein interaction domain / Signal transducer and activator of transcription, linker domain ...STAT3, SH2 domain / STAT transcription factor, DNA-binding, N-terminal / STAT transcription factor, protein interaction / STAT transcription factor, all-alpha domain / STAT transcription factor, DNA-binding / : / STAT transcription factor, coiled-coil domain / STAT protein, DNA binding domain / STAT protein, protein interaction domain / Signal transducer and activator of transcription, linker domain / STAT protein, protein interaction domain / STAT transcription factor, N-terminal domain superfamily / Transcription factor STAT / STAT transcription factor, coiled coil / Mitogen-activated protein (MAP) kinase, ERK1/2 / p53-like transcription factor, DNA-binding / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / SH2 domain / Src homology 2 (SH2) domain profile. / SH2 domain / SH2 domain superfamily / 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-5ID / Mitogen-activated protein kinase 1 / Signal transducer and activator of transcription 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.984 Å
AuthorsKinoshita, T. / Sugiyama, H. / Mori, Y. / Takahashi, N. / Tomonaga, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Identification of allosteric ERK2 inhibitors through in silico biased screening and competitive binding assay
Authors: Kinoshita, T. / Sugiyama, H. / Mori, Y. / Takahashi, N. / Tomonaga, A.
History
DepositionJul 14, 2015Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 10, 2016Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2020Group: Data collection / Database references / Derived calculations
Category: citation / diffrn_source / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Nov 8, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 1
B: allosteric and ATP-competitive inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,1153
Polymers43,7232
Non-polymers3921
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1860 Å2
ΔGint-4 kcal/mol
Surface area17590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.835, 66.465, 116.871
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: 42231.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK1, ERK2, PRKM1, PRKM2 / Plasmid: pGEX 6p-1 / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: P28482, mitogen-activated protein kinase
#2: Protein/peptide allosteric and ATP-competitive inhibitor


Mass: 1491.815 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P40763*PLUS
#3: Chemical ChemComp-5ID / (2R,3R,4S,5R)-2-(4-AMINO-5-IODO-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-5-(HYDROXYMETHYL)TETRAHYDROFURAN-3,4-DIOL / 5-IODOTUBERCIDIN


Mass: 392.150 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H13IN4O4

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 1.95 Å3/Da / Density % sol: 36.82 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: PEG3350, Sodium chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 14, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.98→43.89 Å / Num. obs: 13356 / % possible obs: 99.5 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 14.7
Reflection shellResolution: 2.98→3.16 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.693 / Mean I/σ(I) obs: 2.25 / % possible all: 97.9

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.9_1692)refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2FYS

2fys


Resolution: 2.984→43.886 Å / SU ML: 0.43 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 32.85 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2846 614 4.6 %random selection
Rwork0.2364 ---
obs0.2387 13356 99.55 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.984→43.886 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2812 0 20 0 2832
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032899
X-RAY DIFFRACTIONf_angle_d0.7533923
X-RAY DIFFRACTIONf_dihedral_angle_d15.5271098
X-RAY DIFFRACTIONf_chiral_restr0.027432
X-RAY DIFFRACTIONf_plane_restr0.003494
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.984-3.28430.35791530.28693161X-RAY DIFFRACTION99
3.2843-3.75930.36421580.24123182X-RAY DIFFRACTION100
3.7593-4.73540.23491630.223187X-RAY DIFFRACTION100
4.7354-43.89060.27521400.23483212X-RAY DIFFRACTION100

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