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- PDB-4qp6: Crystal Structure of ERK2 in complex with 5H-pyrrolo[2,3-b]pyrazine -

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Basic information

Entry
Database: PDB / ID: 4qp6
TitleCrystal Structure of ERK2 in complex with 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 / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / Signaling by MAP2K mutants ...phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / Signaling by MAP2K mutants / Signaling by NODAL / ERKs are inactivated / response to epidermal growth factor / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / Regulation of the apoptosome activity / positive regulation of macrophage proliferation / regulation of cellular pH / outer ear morphogenesis / Signaling by LTK in cancer / regulation of Golgi inheritance / labyrinthine layer blood vessel development / ERBB signaling pathway / mammary gland epithelial cell proliferation / trachea formation / Negative feedback regulation of MAPK pathway / positive regulation of peptidyl-threonine phosphorylation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / MAPK1 (ERK2) activation / 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 / response to exogenous dsRNA / face development / lung morphogenesis / positive regulation of telomere maintenance / Recycling pathway of L1 / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / thyroid gland development / steroid hormone receptor signaling pathway / Advanced glycosylation endproduct receptor signaling / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / negative regulation of cell differentiation / regulation of ossification / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate WASPs and WAVEs / JUN kinase activity / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / phosphatase binding / Schwann cell development / Growth hormone receptor signaling / progesterone receptor signaling pathway / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / NPAS4 regulates expression of target genes / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / Transcriptional and post-translational regulation of MITF-M expression and activity / NCAM signaling for neurite out-growth / ERK1 and ERK2 cascade / cellular response to amino acid starvation / insulin-like growth factor receptor signaling pathway / lipopolysaccharide-mediated signaling pathway / ESR-mediated signaling / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / response to nicotine / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR1 signaling / positive regulation of cholesterol biosynthetic process / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / regulation of protein stability / Oncogene Induced Senescence / caveola / Regulation of actin dynamics for phagocytic cup formation / long-term synaptic potentiation
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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
5H-pyrrolo[2,3-b]pyrazine / IMIDAZOLE / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 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 1.2Mar 26, 2025Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / 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_conn.pdbx_leaving_atom_flag / _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)85,5635
Polymers85,2562
Non-polymers3073
Water00
1
A: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8163
Polymers42,6281
Non-polymers1882
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7472
Polymers42,6281
Non-polymers1191
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.533, 82.533, 275.850
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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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: 42627.828 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-36N / 5H-pyrrolo[2,3-b]pyrazine


Mass: 119.124 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H5N3
#3: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
Has protein modificationY

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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: 2.75 Å3/Da / Density % sol: 55.35 %
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

DiffractionMean temperature: 93 K
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: 3.1→50 Å / Num. all: 18239 / Num. obs: 18239 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 3.1→3.11 Å / % possible all: 100

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.1→49.273 Å / SU ML: 0.34 / σ(F): 1.44 / Phase error: 24.09 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2509 1649 5 %
Rwork0.2128 --
obs0.2147 -99.91 %
all-18239 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.1→49.273 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5533 0 23 0 5556
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0035693
X-RAY DIFFRACTIONf_angle_d0.8477711
X-RAY DIFFRACTIONf_dihedral_angle_d13.9492149
X-RAY DIFFRACTIONf_chiral_restr0.064842
X-RAY DIFFRACTIONf_plane_restr0.003990
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1-3.19120.361310.30112637X-RAY DIFFRACTION100
3.1912-3.29420.28951370.28012621X-RAY DIFFRACTION100
3.2942-3.41190.31741330.26252611X-RAY DIFFRACTION100
3.4119-3.54850.25051550.24512587X-RAY DIFFRACTION100
3.5485-3.70990.29171370.21722610X-RAY DIFFRACTION100
3.7099-3.90540.22471590.19392609X-RAY DIFFRACTION100
3.9054-4.150.22751340.1952602X-RAY DIFFRACTION100
4.15-4.47020.22171690.17832576X-RAY DIFFRACTION100
4.4702-4.91970.25291500.17862595X-RAY DIFFRACTION100
4.9197-5.63080.20631320.20532626X-RAY DIFFRACTION100
5.6308-7.09080.3014990.22642660X-RAY DIFFRACTION100
7.0908-49.27930.22231130.19562625X-RAY DIFFRACTION100
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)
11.93-0.35740.03021.38740.22580.6845-0.3235-0.5365-0.31860.37040.4520.30110.0533-0.04210.08460.34020.20080.06970.41920.13580.3803-21.5075-28.7997-18.4463
22.4371-0.25680.56641.5197-0.84381.6894-0.1614-0.1076-0.0149-0.05350.0413-0.1549-0.0210.1435-0.01610.15880.00190.0170.184-0.01170.21454.9421-31.6286-27.9225
31.0723-0.52730.37060.7368-0.52810.6317-0.0495-0.1118-0.22790.24260.0055-0.34830.3650.3506-0.00620.36370.1289-0.09150.30580.02510.29153.9209-61.797-53.3162
40.6255-0.07030.86631.34370.91772.9206-0.1641-0.01480.0377-0.03410.04720.0989-0.3274-0.2112-0.04680.267-0.0013-0.01520.2493-0.00570.2566-12.3941-42.0217-62.8109
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 12:108 OR RESID 335:360 ) )A12 - 108
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 12:108 OR RESID 335:360 ) )A335 - 360
3X-RAY DIFFRACTION2( CHAIN A AND RESID 109:334 )A109 - 334
4X-RAY DIFFRACTION3( CHAIN B AND ( RESID 12:108 OR RESID 335:357 ) )B12 - 108
5X-RAY DIFFRACTION3( CHAIN B AND ( RESID 12:108 OR RESID 335:357 ) )B335 - 357
6X-RAY DIFFRACTION4( CHAIN B AND RESID 109:334 )B109 - 334

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