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- PDB-5bui: ERK2 complexed with 2-pyridiyl tetrahydroazaindazole -

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Basic information

Entry
Database: PDB / ID: 5bui
TitleERK2 complexed with 2-pyridiyl 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 / 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 / cytosine metabolic process / ERKs are inactivated ...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 / 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 / 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 / androgen receptor signaling pathway / pseudopodium / RUNX2 regulates osteoblast differentiation / Recycling pathway of L1 / progesterone receptor signaling pathway / 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 mediated 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 / Nuclear events stimulated by ALK signaling in cancer / mitogen-activated protein kinase / phosphatase binding / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Schwann cell development / stress-activated MAPK cascade / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of telomerase activity / cellular response to cadmium ion / cellular response to amino acid starvation / positive regulation of telomere maintenance via telomerase / ERK1 and ERK2 cascade / NPAS4 regulates expression of target genes / 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 / FCGR3A-mediated phagocytosis / 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 / response to nicotine / Signaling by high-kinase activity BRAF mutants / 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-4V9 / NICKEL (II) ION / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.12 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 / Source and taxonomy
Revision 1.2Sep 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 / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model / pdbx_struct_conn_angle / pdbx_struct_oper_list / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_symmetry

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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)41,8213
Polymers41,4681
Non-polymers3532
Water5,332296
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area110 Å2
ΔGint-6 kcal/mol
Surface area16240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.830, 71.250, 120.060
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) / Plasmid: PDEST1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-NI / NICKEL (II) ION / Nickel


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#3: Chemical ChemComp-4V9 / 3-(4-fluorophenyl)-5-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine


Mass: 294.326 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15FN4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 296 / 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 : 200MM CALCIUM ACETATE; 20% PEG3350 PROTEIN SOLUTION : 20.7MG/ML IN 20MM TRIS PH 7.5, 150MM NACL,1MM TCEP(NO GLYCEROL) FORMATION METHOD : CO-CRYSTALLIZATION PROTOCOL : ...Details: RESERVOIR SOLUTION : 200MM CALCIUM ACETATE; 20% PEG3350 PROTEIN SOLUTION : 20.7MG/ML IN 20MM TRIS PH 7.5, 150MM NACL,1MM TCEP(NO GLYCEROL) FORMATION METHOD : CO-CRYSTALLIZATION PROTOCOL : COMPOUND (NVP-LLG040) WAS INCUBATED WITH THE PROTEIN AT 1MM FINAL CONCENTRATION BEFORE SETUP. EQUAL VOLUMES OF PROTEIN AND CRYSTALLANT WERE ADDED TO COVERSLIP METHOD: VAPOR DIFFUSION - HANGING DROP TEMPERATURE: 291.0 CRYO PROTOCOL: MOTHER LIQUOR (200MM CALCIUM ACETATE; 20% PEG3350) + 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 315 / Detector: CCD / Date: Sep 7, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.12→45.91 Å / Num. obs: 21369 / % possible obs: 97.3 % / Redundancy: 4.3 % / Biso Wilson estimate: 32.17 Å2 / Rmerge(I) obs: 0.068 / Net I/σ(I): 14.2
Reflection shellResolution: 2.12→2.23 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.372 / Mean I/σ(I) obs: 3.5 / % possible all: 95.1

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
BUSTER2.11.2refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OJG

2ojg


Resolution: 2.12→22.7 Å / SU R Cruickshank DPI: 0.21 / Cross valid method: FREE R-VALUE / SU R Blow DPI: 0.237 / SU Rfree Blow DPI: 0.186 / SU Rfree Cruickshank DPI: 0.18
RfactorNum. reflection% reflectionSelection details
Rfree0.2218 1095 5.14 %RANDOM
Rwork0.1693 ---
obs0.172 21324 96.76 %-
Displacement parametersBiso mean: 34.81 Å2
Refinement stepCycle: LAST / Resolution: 2.12→22.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2743 0 23 296 3062
LS refinement shellResolution: 2.12→2.22 Å
RfactorNum. reflection% reflection
Rfree0.2588 154 5.63 %
Rwork0.1897 2733 -
obs--96.76 %
Refinement TLS params.Method: refined / Origin x: -6.2518 Å / Origin y: -3.5743 Å / Origin z: 20.3778 Å
111213212223313233
T-0.0477 Å20.0144 Å20.0374 Å2--0.0577 Å20.0187 Å2---0.0487 Å2
L0.6941 °20.1707 °20.2083 °2-0.3711 °20.1044 °2--1.479 °2
S-0.0033 Å °0.1017 Å °0.0555 Å °0.0896 Å °-0.0507 Å °0.0645 Å °0.1662 Å °0.0827 Å °0.054 Å °
Refinement TLS groupSelection details: { A|9 - A|356 }

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