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- PDB-8u8j: Co-crystal structure of phosphorylated ERK2 in complex with ERK1/... -

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Basic information

Entry
Database: PDB / ID: 8u8j
TitleCo-crystal structure of phosphorylated ERK2 in complex with ERK1/2 inhibitor #16
ComponentsMitogen-activated protein kinase 1
KeywordsSIGNALING PROTEIN / TRANSFERASE/INHIBITOR / protein kinase / ATP-competitive Inhibitor / conformation selection / 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 / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / 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 telomerase activity / 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 / Negative regulation of FGFR2 signaling / FCERI mediated MAPK activation / Negative regulation of FGFR4 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / B cell receptor signaling pathway / peptidyl-threonine phosphorylation / 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. / 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. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / 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
Similarity search - Domain/homology
: / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsAnderson, J.W. / Vigers, G.P.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Elife / Year: 2024
Title: Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2.
Authors: Anderson, J.W. / Vaisar, D. / Jones, D.N. / Pegram, L.M. / Vigers, G.P. / Chen, H. / Moffat, J.G. / Ahn, N.G.
History
DepositionSep 18, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID

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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)41,4962
Polymers41,1341
Non-polymers3621
Water4,161231
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.100, 76.660, 151.970
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Mitogen-activated protein kinase 1 / MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform ...MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK / Mitogen-activated protein kinase 2 / MAP kinase 2 / MAPK 2


Mass: 41134.031 Da / Num. of mol.: 1 / Mutation: A5S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK1, ERK2, PRKM1, PRKM2
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-WAL / (4M)-4-{(4R)-3-[(2S)-2-methylbutyl][1,2,4]triazolo[4,3-a]pyridin-7-yl}-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine


Mass: 362.432 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22N8 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Sequence detailsThe residue numbering in Uniprot P28482 is off by two relative to this residue numbering, such that ...The residue numbering in Uniprot P28482 is off by two relative to this residue numbering, such that Asp-167 in the Uniprot entry is Asp-165 in this entry. Also, the construct used in this structure determination lacks the MAAAAA at the amino-terminus, and has the following alanine substituted by a serine.

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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: 2.96 Å3/Da / Density % sol: 58.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 9 / Details: 36% PEG 3350, 0.1M Tris pH 9.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Aug 27, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. obs: 25654 / % possible obs: 86.7 % / Redundancy: 5.65 % / Biso Wilson estimate: 27.39 Å2 / Rpim(I) all: 0.063 / Rsym value: 0.147 / Net I/σ(I): 6.53
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 6 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2959 / Rpim(I) all: 0.139 / Rsym value: 0.335 / % possible all: 70

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→19.56 Å / SU ML: 0.2518 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.1547
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2266 1299 5.08 %
Rwork0.1773 24261 -
obs0.1798 25560 86.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.69 Å2
Refinement stepCycle: LAST / Resolution: 2.1→19.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2873 0 27 231 3131
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00722973
X-RAY DIFFRACTIONf_angle_d0.85894034
X-RAY DIFFRACTIONf_chiral_restr0.0512436
X-RAY DIFFRACTIONf_plane_restr0.0083516
X-RAY DIFFRACTIONf_dihedral_angle_d13.3456400
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.180.28551200.20012144X-RAY DIFFRACTION70.09
2.18-2.280.27111090.17992130X-RAY DIFFRACTION69.82
2.28-2.40.21651110.1872205X-RAY DIFFRACTION71.84
2.4-2.550.25281170.19352486X-RAY DIFFRACTION80.14
2.55-2.750.22911540.19522811X-RAY DIFFRACTION91.09
2.75-3.030.28931780.20282967X-RAY DIFFRACTION96.06
3.03-3.460.26171630.18523091X-RAY DIFFRACTION98.91
3.46-4.350.17791620.15313141X-RAY DIFFRACTION99.43
4.35-19.560.19931850.16733286X-RAY DIFFRACTION99.51

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