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- PDB-5buj: ERK2 complexed with a N-H tetrahydroazaindazole -

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Basic information

Entry
Database: PDB / ID: 5buj
TitleERK2 complexed with a N-H tetrahydroazaindazole
ComponentsMitogen-activated protein kinase 1
KeywordsTransferase/Transferase inhibitor / ERK2 / Mitogen-activated protein kinase 1 / ATP inhibitor / Transferase-Transferase inhibitor complex
Function / homology
Function and homology information


phospho-PLA2 pathway / Signaling by MAPK mutants / Suppression of apoptosis / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / ERKs are inactivated ...phospho-PLA2 pathway / Signaling by MAPK mutants / Suppression of apoptosis / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / ERKs are inactivated / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / regulation of cellular pH / positive regulation of macrophage proliferation / outer ear morphogenesis / Regulation of the apoptosome activity / regulation of Golgi inheritance / ERBB signaling pathway / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / trachea formation / regulation of early endosome to late endosome transport / Negative feedback regulation of MAPK pathway / regulation of cytoskeleton organization / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / positive regulation of macrophage chemotaxis / response to exogenous dsRNA / lung morphogenesis / ERBB2-ERBB3 signaling pathway / face development / Recycling pathway of L1 / Activation of the AP-1 family of transcription factors / androgen receptor signaling pathway / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / pseudopodium / progesterone receptor signaling pathway / positive regulation of telomere capping / negative regulation of cell differentiation / MAPK1 (ERK2) activation / Bergmann glial cell differentiation / thyroid gland development / Advanced glycosylation endproduct receptor signaling / steroid hormone mediated signaling pathway / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate WASPs and WAVEs / regulation of ossification / MAP kinase activity / phosphatase binding / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Nuclear events stimulated by ALK signaling in cancer / stress-activated MAPK cascade / Schwann cell development / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of telomerase activity / ERK1 and ERK2 cascade / cellular response to cadmium ion / positive regulation of telomere maintenance via telomerase / cellular response to amino acid starvation / myelination / NPAS4 regulates expression of target genes / 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 / response to nicotine / positive regulation of peptidyl-threonine phosphorylation / Signal transduction by L1 / Regulation of PTEN gene transcription / long-term synaptic potentiation / caveola / Negative regulation of FGFR3 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / B cell receptor signaling pathway / Spry regulation of FGF signaling / peptidyl-threonine phosphorylation / Signaling by high-kinase activity BRAF mutants / regulation of protein stability / MAP2K and MAPK activation / 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-4VB / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsBellamacina, C.R. / Shu, W. / Bussiere, D.E. / Bagdanoff, J.T.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Ligand efficient tetrahydro-pyrazolopyridines as inhibitors of ERK2 kinase.
Authors: Bagdanoff, J.T. / Jain, R. / Han, W. / Poon, D. / Lee, P.S. / Bellamacina, C. / Lindvall, M.
History
DepositionJun 3, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 12, 2015Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / 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)41,7612
Polymers41,4681
Non-polymers2931
Water7,098394
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.810, 71.266, 120.069
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) / Strain (production host): BL21(DE3)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-4VB / 4-[3-(pyridin-4-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]pyridin-2(1H)-one


Mass: 293.323 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15N5O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 394 / 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: 2.26 Å3/Da / Density % sol: 45.58 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: RESERVOIR SOLUTION: 20% PEG 3350, 20MM MAGNESIUM FORMATE, PROTEIN SOLUTION 20MM TRIS PH 7.5, 150 MM NACL, 1MM TCEP FORMATION METHOD: SOAKING PROTOCOL: Low affinity compound WAS INCUBATED ...Details: RESERVOIR SOLUTION: 20% PEG 3350, 20MM MAGNESIUM FORMATE, PROTEIN SOLUTION 20MM TRIS PH 7.5, 150 MM NACL, 1MM TCEP FORMATION METHOD: SOAKING PROTOCOL: Low affinity compound WAS INCUBATED WITH THE PROTEIN AT 2MM FINAL CONCENTRATION BEFORE SETUP. EQUAL VOLUMES OF PROTEIN AND CRYSTALLANT WERE ADDED TO COVER-SLIP. CRYSTAL APPEAR AFTER SEVEAL DAYS. EXCHANGE SOAKING WAS PERFORMED USING 2MM COMPOUND AT LEAST OVERNIGHT. METHOD: VAPOR DIFFUSION - HANGING DROP TEMPERATURE: 291.0 CRYO PROTOCOL: MOTHER LIQUOR (200MM AMMONIUM SULFATE; 30% PEG MME 5K) + 20% GLYCEROL

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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 315r / Detector: CCD / Date: May 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 32649 / % possible obs: 99.9 % / Redundancy: 5.9 % / Biso Wilson estimate: 25.14 Å2 / Rmerge(I) obs: 0.078 / Net I/σ(I): 20.4
Reflection shellResolution: 1.85→1.92 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.707 / Mean I/σ(I) obs: 2.08 / % possible all: 98.8

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
BUSTER2.11.2refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1QNZC

Resolution: 1.85→24.45 Å / SU R Cruickshank DPI: 0.124 / Cross valid method: FREE R-VALUE / SU R Blow DPI: 0.137 / SU Rfree Blow DPI: 0.124 / SU Rfree Cruickshank DPI: 0.118
RfactorNum. reflection% reflectionSelection details
Rfree0.2064 1650 5.07 %RANDOM
Rwork0.1712 ---
obs0.173 32563 99.01 %-
Displacement parametersBiso mean: 30.08 Å2
Refinement stepCycle: LAST / Resolution: 1.85→24.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2679 0 22 394 3095
LS refinement shellResolution: 1.85→1.91 Å
RfactorNum. reflection% reflection
Rfree0.234 127 4.74 %
Rwork0.2166 2552 -
obs--99.01 %
Refinement TLS params.Method: refined / Origin x: -6.8148 Å / Origin y: -3.2491 Å / Origin z: 20.066 Å
111213212223313233
T-0.0505 Å20.014 Å20.0129 Å2--0.0496 Å20.0083 Å2---0.0365 Å2
L0.7266 °20.1654 °20.1436 °2-0.2391 °2-0.0963 °2--1.2623 °2
S-0.0296 Å °0.091 Å °0.0377 Å °0.0183 Å °-0.0246 Å °0.0065 Å °0.0981 Å °0.0689 Å °0.0542 Å °
Refinement TLS groupSelection details: '{ A|* }'

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