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- PDB-4qp8: Crystal Structure of ERK2 in complex with 2-(1H-pyrazol-4-yl)-7-(... -

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Basic information

Entry
Database: PDB / ID: 4qp8
TitleCrystal Structure of ERK2 in complex with 2-(1H-pyrazol-4-yl)-7-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine
ComponentsMitogen-activated protein kinase 1
Keywordstransferase/transferase 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 / 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-362 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.446 Å
AuthorsYin, J. / Wang, W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors.
Authors: Burdick, D.J. / Wang, S. / Heise, C. / Pan, B. / Drummond, J. / Yin, J. / Goeser, L. / Magnuson, S. / Blaney, J. / Moffat, J. / Wang, W. / Chen, H.
History
DepositionJun 22, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 23, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 16, 2015Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 1
B: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,6224
Polymers85,0982
Non-polymers5252
Water2,468137
1
A: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8112
Polymers42,5491
Non-polymers2621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8112
Polymers42,5491
Non-polymers2621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)59.241, 67.185, 87.524
Angle α, β, γ (deg.)90.00, 102.12, 90.00
Int Tables number4
Space group name H-MP1211

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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: 42548.855 Da / Num. of mol.: 2
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-362 / 2-(1H-pyrazol-4-yl)-7-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine


Mass: 262.269 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H10N6
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 137 / 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 Å3/Da / Density % sol: 38.54 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 10% PEG3350, 0.2 M proline, and 0.1 M HEPES pH7.5, in a 24-well Linbro plates incubated at 4C, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 25, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.446→50 Å / Num. all: 24934 / Num. obs: 24685 / % possible obs: 99 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.446→43.882 Å / SU ML: 0.31 / σ(F): 1.34 / Phase error: 26.32 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2488 1276 5.18 %random
Rwork0.204 ---
all0.2062 24934 --
obs0.2062 24643 98.36 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.446→43.882 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5492 0 40 137 5669
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0035666
X-RAY DIFFRACTIONf_angle_d0.717674
X-RAY DIFFRACTIONf_dihedral_angle_d13.7552144
X-RAY DIFFRACTIONf_chiral_restr0.055840
X-RAY DIFFRACTIONf_plane_restr0.003984
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4457-2.54360.2911350.23982391X-RAY DIFFRACTION92
2.5436-2.65940.33971420.25022592X-RAY DIFFRACTION99
2.6594-2.79950.30751340.2412623X-RAY DIFFRACTION99
2.7995-2.97490.29671520.24592589X-RAY DIFFRACTION99
2.9749-3.20450.2381270.22492601X-RAY DIFFRACTION99
3.2045-3.52690.24791400.22282624X-RAY DIFFRACTION99
3.5269-4.03690.22421490.18072610X-RAY DIFFRACTION100
4.0369-5.08490.23411520.17382637X-RAY DIFFRACTION100
5.0849-43.88860.22391450.18862700X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.3889-0.7344-0.00642.1035-0.8181.5901-0.0937-0.1126-0.198-0.1183-0.012-0.26570.40810.3205-0.00010.39080.0733-0.0640.5732-0.030.440245.9641-47.869636.1739
22.74330.04680.04953.1462-0.3693.11730.01540.0066-0.199-0.3785-0.053-0.05810.2607-0.08660.00630.12180.01030.02770.066-0.04390.064124.272-33.580826.614
31.25910.55831.02241.6129-0.03522.20670.127-0.09250.00030.0462-0.06860.0350.1712-0.3824-00.38910.0042-0.00740.46080.08720.38454.2121-14.00186.5724
42.6874-0.09530.3562.3913-0.2232.88230.1369-0.20650.34640.0110.019-0.0278-0.3057-0.05470.10610.1947-0.01970.09740.0488-0.06230.271425.6623-0.807416.9471
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 10:108 OR RESID 335:355 ) )A10 - 108
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 10:108 OR RESID 335:355 ) )A335 - 355
3X-RAY DIFFRACTION2( CHAIN A AND RESID 109:334 )A109 - 334
4X-RAY DIFFRACTION3( CHAIN B AND ( RESID 11:108 OR RESID 335:355 ) )B11 - 108
5X-RAY DIFFRACTION3( CHAIN B AND ( RESID 11:108 OR RESID 335:355 ) )B335 - 355
6X-RAY DIFFRACTION4( CHAIN B AND RESID 109:334 )B109 - 334

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