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- PDB-5ngu: Human Erk2 with an Erk1/2 inhibitor -

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Basic information

Entry
Database: PDB / ID: 5ngu
TitleHuman Erk2 with an Erk1/2 inhibitor
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE / Erk2 / kinase / inhibitor / oncology
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 / ERKs are inactivated / cytosine metabolic process ...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 / ERKs are inactivated / cytosine metabolic process / Signaling by MAP2K mutants / Signaling by NODAL / 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 / positive regulation of telomere maintenance / lung morphogenesis / 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 / negative regulation of cell differentiation / MAP kinase activity / regulation of ossification / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate WASPs and WAVEs / Regulation of HSF1-mediated heat shock response / 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
Chem-8X2 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.74 Å
AuthorsDebreczeni, J.E. / Ward, R.A. / Bethel, P. / Cook, C. / Davies, E. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. ...Debreczeni, J.E. / Ward, R.A. / Bethel, P. / Cook, C. / Davies, E. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Hopcroft, P. / Howard, T.D. / Hudson, J. / James, M. / Jones, C.D. / Jones, C.R. / Lamont, S. / Lewis, R. / Lindsay, N. / Roberts, K. / Simpson, I. / StGallay, S. / Swallow, S. / Tonge, M.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point.
Authors: Ward, R.A. / Bethel, P. / Cook, C. / Davies, E. / Debreczeni, J.E. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Griffin, N. / Hanson, L. / Hopcroft, P. / ...Authors: Ward, R.A. / Bethel, P. / Cook, C. / Davies, E. / Debreczeni, J.E. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Griffin, N. / Hanson, L. / Hopcroft, P. / Howard, T.D. / Hudson, J. / James, M. / Jones, C.D. / Jones, C.R. / Lamont, S. / Lewis, R. / Lindsay, N. / Roberts, K. / Simpson, I. / St-Gallay, S. / Swallow, S. / Tang, J. / Tonge, M. / Wang, Z. / Zhai, B.
History
DepositionMar 20, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 19, 2017Provider: repository / Type: Initial release
Revision 1.1May 10, 2017Group: Database references
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)44,5814
Polymers43,9851
Non-polymers5963
Water25214
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area400 Å2
ΔGint-29 kcal/mol
Surface area15590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.980, 71.050, 60.610
Angle α, β, γ (deg.)90.00, 110.02, 90.00
Int Tables number4
Space group name H-MP1211

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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: 43985.414 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)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-8X2 / 2-[2-[[4-(4-methylpiperazin-1-yl)phenyl]amino]pyrimidin-4-yl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one


Mass: 403.480 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25N7O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O
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: 2.25 Å3/Da / Density % sol: 45.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 30% PegMME2K, 100mM HEPES pH 7.6, 200mM Ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.74→35.5 Å / Num. obs: 4698 / % possible obs: 97.3 % / Redundancy: 3.2 % / Biso Wilson estimate: 68.28 Å2 / Rmerge(I) obs: 0.141 / Rpim(I) all: 0.135 / Net I/σ(I): 6.9
Reflection shellResolution: 2.74→2.81 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.537 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 743 / Rpim(I) all: 0.506 / % possible all: 97.9

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZZN

4zzn


Resolution: 2.74→35.5 Å / Cor.coef. Fo:Fc: 0.883 / Cor.coef. Fo:Fc free: 0.867 / Rfactor Rfree error: 0.01 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.364
RfactorNum. reflection% reflectionSelection details
Rfree0.262 485 4.81 %RANDOM
Rwork0.267 ---
obs0.266 10077 97.2 %-
Displacement parametersBiso mean: 53.34 Å2
Baniso -1Baniso -2Baniso -3
1-8.1864 Å20 Å21.838 Å2
2---14.2351 Å20 Å2
3---6.0487 Å2
Refine analyzeLuzzati coordinate error obs: 0.52 Å
Refinement stepCycle: 1 / Resolution: 2.74→35.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2692 0 50 14 2756
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0112810HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.243825HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d949SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes65HARMONIC2
X-RAY DIFFRACTIONt_gen_planes435HARMONIC5
X-RAY DIFFRACTIONt_it2810HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.35
X-RAY DIFFRACTIONt_other_torsion20.68
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion368SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3205SEMIHARMONIC4
LS refinement shellResolution: 2.74→3.06 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.379 136 4.75 %
Rwork0.324 2727 -
all0.327 2863 -
obs--97.68 %
Refinement TLS params.Method: refined / Origin x: -5.1618 Å / Origin y: 8.6617 Å / Origin z: 47.0199 Å
111213212223313233
T-0.1829 Å20.0175 Å20.1342 Å2--0.0676 Å2-0.0005 Å2---0.0123 Å2
L1.428 °20.2224 °20.62 °2-0.7027 °20.0385 °2--2.3619 °2
S-0.0724 Å °0.0208 Å °0.0887 Å °-0.0872 Å °-0.005 Å °0.0111 Å °-0.0874 Å °0.147 Å °0.0775 Å °
Refinement TLS groupSelection details: { A|* }

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