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

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Basic information

Entry
Database: PDB / ID: 5nhp
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 / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / 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 / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / ERKs are inactivated / cytosine metabolic process / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / Regulation of the apoptosome activity / outer ear morphogenesis / regulation of cellular pH / 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 / progesterone receptor signaling pathway / androgen receptor signaling pathway / RUNX2 regulates osteoblast differentiation / pseudopodium / Recycling pathway of L1 / 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 receptor signaling pathway / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate NADPH Oxidases / Regulation of HSF1-mediated heat shock response / MAP kinase activity / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / mitogen-activated protein kinase / phosphatase binding / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Nuclear events stimulated by ALK signaling in cancer / Schwann cell development / Growth hormone receptor signaling / stress-activated MAPK cascade / lipopolysaccharide-mediated signaling pathway / : / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / NPAS4 regulates expression of target genes / ERK1 and ERK2 cascade / cellular response to amino acid starvation / 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 / Negative regulation of FGFR4 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / peptidyl-threonine phosphorylation / B cell receptor signaling pathway / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / response to nicotine / 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-8XK / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.99 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 22, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 19, 2017Provider: repository / Type: Initial release
Revision 1.1May 10, 2017Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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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)44,4834
Polymers43,9091
Non-polymers5743
Water3,657203
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area370 Å2
ΔGint-27 kcal/mol
Surface area15520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.791, 71.115, 61.032
Angle α, β, γ (deg.)90.00, 111.03, 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: 43909.297 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-8XK / 5-(2-methoxyethyl)-1-methyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-6,7-dihydropyrrolo[3,2-c]pyridin-4-one


Mass: 381.432 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23N7O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 203 / 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: 2.52 Å3/Da / Density % sol: 51.1 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
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: ESRF / Beamline: ID29 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.99→45.54 Å / Num. obs: 26082 / % possible obs: 97.8 % / Redundancy: 3.3 % / Biso Wilson estimate: 32.82 Å2 / Rmerge(I) obs: 0.078 / Rsym value: 0.078 / Net I/σ(I): 11.5
Reflection shellResolution: 1.994→2.001 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.688 / Mean I/σ(I) obs: 2.2 / Rsym value: 0.688 / % possible all: 94.8

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION January 10data reduction
Aimless(version 0.3.6)data scaling
SCALA6.4data scaling
BUSTER2.11.6refinement
PHASERphasing
CCP46.4data scaling
RefinementResolution: 1.99→44.46 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.901 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.18 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.183 / SU Rfree Blow DPI: 0.149 / SU Rfree Cruickshank DPI: 0.149
RfactorNum. reflection% reflectionSelection details
Rfree0.221 1651 6.33 %RANDOM
Rwork0.198 ---
obs0.199 26063 97.1 %-
Displacement parametersBiso mean: 35.2 Å2
Baniso -1Baniso -2Baniso -3
1-4.8589 Å20 Å21.5121 Å2
2---1.794 Å20 Å2
3----3.0649 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 1.99→44.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2692 0 38 203 2933
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0062797HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.933807HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d949SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes67HARMONIC2
X-RAY DIFFRACTIONt_gen_planes400HARMONIC5
X-RAY DIFFRACTIONt_it2797HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.29
X-RAY DIFFRACTIONt_other_torsion18.15
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion366SEMIHARMONIC5
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_contact3490SEMIHARMONIC4
LS refinement shellResolution: 1.99→2.07 Å / Rfactor Rfree error: 0 / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.299 165 6.04 %
Rwork0.298 2567 -
all0.298 2732 -
obs--90.66 %
Refinement TLS params.Method: refined / Origin x: -6.0234 Å / Origin y: 8.6615 Å / Origin z: 47.5601 Å
111213212223313233
T-0.0633 Å2-0.0181 Å20.0419 Å2--0.1141 Å20.0179 Å2---0.0727 Å2
L0.9827 °20.2773 °20.4385 °2-0.5016 °20.3961 °2--1.1542 °2
S-0.0788 Å °0.0976 Å °0.0725 Å °-0.0683 Å °0.0382 Å °0.0351 Å °-0.0844 Å °0.0591 Å °0.0406 Å °
Refinement TLS groupSelection details: { A|* }

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