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- PDB-6rq4: Inhibitor of ERK2 -

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Basic information

Entry
Database: PDB / ID: 6rq4
TitleInhibitor of ERK2
ComponentsMitogen-activated protein kinase 1
KeywordsSIGNALING PROTEIN / protein kinase ATP-binding site serine/threonine kinase
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 / response to epidermal growth factor ...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 / response to epidermal growth factor / ERKs are inactivated / 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 / Signaling by LTK in cancer / 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 / ERBB2-ERBB3 signaling pathway / lung morphogenesis / response to exogenous dsRNA / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / regulation of cytoskeleton organization / face development / androgen receptor signaling pathway / pseudopodium / RUNX2 regulates osteoblast differentiation / : / positive regulation of telomere capping / Recycling pathway of L1 / MAPK1 (ERK2) activation / Bergmann glial cell differentiation / thyroid gland development / negative regulation of cell differentiation / Advanced glycosylation endproduct receptor signaling / steroid hormone receptor signaling pathway / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / Regulation of HSF1-mediated heat shock response / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / mitogen-activated protein kinase / RHO GTPases Activate WASPs and WAVEs / phosphatase binding / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Transcriptional and post-translational regulation of MITF-M expression and activity / progesterone receptor signaling pathway / Schwann cell development / Nuclear events stimulated by ALK signaling in cancer / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / stress-activated MAPK cascade / positive regulation of telomere maintenance via telomerase / phosphotyrosine residue binding / NPAS4 regulates expression of target genes / cellular response to cadmium ion / myelination / ERK1 and ERK2 cascade / cellular response to amino acid starvation / NCAM signaling for neurite out-growth / ESR-mediated signaling / RNA polymerase II CTD heptapeptide repeat kinase activity / insulin-like growth factor receptor signaling pathway / thymus development / positive regulation of peptidyl-threonine phosphorylation / Signal transduction by L1 / Regulation of PTEN gene transcription / long-term synaptic potentiation / response to nicotine / peptidyl-threonine phosphorylation / Negative regulation of FGFR2 signaling / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Negative regulation of FGFR3 signaling / B cell receptor signaling pathway / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / 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 / caveola / Oncogene Induced Senescence
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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
Similarity search - Domain/homology
Chem-KE8 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.96 Å
AuthorsO'Reilly, M.
CitationJournal: Mol.Cancer Ther. / Year: 2020
Title: Dual-Mechanism ERK1/2 Inhibitors Exploit a Distinct Binding Mode to Block Phosphorylation and Nuclear Accumulation of ERK1/2.
Authors: Kidger, A.M. / Munck, J.M. / Saini, H.K. / Balmanno, K. / Minihane, E. / Courtin, A. / Graham, B. / O'Reilly, M. / Odle, R. / Cook, S.J.
History
DepositionMay 15, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 19, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year / _citation_author.identifier_ORCID

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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)43,1023
Polymers42,5521
Non-polymers5502
Water5,999333
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint-14 kcal/mol
Surface area16140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.853, 70.933, 60.325
Angle α, β, γ (deg.)90.00, 109.92, 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: 42551.922 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.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-KE8 / 6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one


Mass: 453.560 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H27N7O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 333 / 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: 2.31 Å3/Da / Density % sol: 46.74 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 0.25M (NH4)2SO4 33% MPEG 2000 0.02M Mercaptoethanol 0.1M pH=7.2 HEPES/NaOH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.5418 Å
DetectorType: DECTRIS EIGER X 1M / Detector: PIXEL / Date: Sep 6, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.96→48.85 Å / Num. obs: 24063 / % possible obs: 86.3 % / Redundancy: 3.3 % / Biso Wilson estimate: 28.76 Å2 / Rrim(I) all: 0.055 / Net I/σ(I): 10.9
Reflection shellResolution: 1.96→2 Å / Mean I/σ(I) obs: 0.7 / Num. unique obs: 1217 / Rrim(I) all: 2.02 / % possible all: 73.9

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.96→35.47 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.912 / SU R Cruickshank DPI: 0.807 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.2 / SU Rfree Blow DPI: 0.175 / SU Rfree Cruickshank DPI: 0.171
RfactorNum. reflection% reflectionSelection details
Rfree0.232 1255 5.22 %RANDOM
Rwork0.175 ---
obs0.178 24034 86.2 %-
Displacement parametersBiso mean: 41.782 Å2
Baniso -1Baniso -2Baniso -3
1--0.9284 Å20 Å20.0618 Å2
2---1.116 Å20 Å2
3---2.0444 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: 1 / Resolution: 1.96→35.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2703 0 47 333 3083
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0125599HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0810139HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1243SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes890HARMONIC16
X-RAY DIFFRACTIONt_it5593HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.4
X-RAY DIFFRACTIONt_other_torsion16.51
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion363SEMIHARMONIC5
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_contact6423SEMIHARMONIC4
LS refinement shellResolution: 1.96→1.97 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.4783 -4.99 %
Rwork0.3225 457 -
all0.3293 481 -
obs--83.1 %
Refinement TLS params.Method: refined / Origin x: -2.1004 Å / Origin y: 3.0865 Å / Origin z: 37.197 Å
111213212223313233
T-0.1058 Å20.0148 Å20.01 Å2--0.1134 Å2-0.0557 Å2---0.0612 Å2
L2.0091 °2-0.8258 °20.606 °2-1.4606 °2-0.3524 °2--1.0108 °2
S-0.1768 Å °-0.2318 Å °0.2215 Å °0.2039 Å °0.1371 Å °-0.1462 Å °-0.0904 Å °-0.1146 Å °0.0397 Å °
Refinement TLS groupSelection details: { A|19 - A|365 }

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