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- PDB-8ao8: Specific covalent inhibitor(9) of ERK2 -

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Basic information

Entry
Database: PDB / ID: 8ao8
TitleSpecific covalent inhibitor(9) of ERK2
ComponentsMitogen-activated protein kinase 1
KeywordsSIGNALING PROTEIN / serine-threonine kinase / transcriptional repressor / cell cycle / ATP binding
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-N5U / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.697 Å
AuthorsCleasby, A.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Not funded United Kingdom
CitationJournal: J.Med.Chem. / Year: 2022
Title: X-ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor.
Authors: St Denis, J.D. / Chessari, G. / Cleasby, A. / Cons, B.D. / Cowan, S. / Dalton, S.E. / East, C. / Murray, C.W. / O'Reilly, M. / Peakman, T. / Rapti, M. / Stow, J.L.
History
DepositionAug 8, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 28, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 2.0May 24, 2023Group: Non-polymer description / Category: chem_comp / Item: _chem_comp.formula

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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)42,9935
Polymers42,5521
Non-polymers4414
Water6,251347
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area430 Å2
ΔGint-9 kcal/mol
Surface area16520 Å2
Unit cell
Length a, b, c (Å)48.626, 70.118, 60.473
Angle α, β, γ (deg.)90.000, 109.420, 90.000
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 BL21(DE3) (bacteria)
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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-N5U / 1-[(2~{R})-2-(3-methylimidazol-4-yl)piperidin-1-yl]propan-1-one


Mass: 221.299 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H19N3O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 347 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.28 Å3/Da / Density % sol: 46.17 %
Crystal growTemperature: 293 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-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Nov 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.697→57.03 Å / Num. obs: 34587 / % possible obs: 87 % / Redundancy: 2.05 % / Rrim(I) all: 0.09 / Net I/σ(I): 8.8
Reflection shellResolution: 1.697→1.747 Å / Num. unique obs: 828 / Rrim(I) all: 0.343

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (16-JUL-2021)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.697→57.03 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.924 / SU R Cruickshank DPI: 0.176 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.127 / SU Rfree Blow DPI: 0.12 / SU Rfree Cruickshank DPI: 0.117
Details: HYDROGENS WERE FULLY REFINED U VALUES : WITH TLS ADDED WITH FULL OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT ...Details: HYDROGENS WERE FULLY REFINED U VALUES : WITH TLS ADDED WITH FULL OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2114 1765 5.16 %RANDOM
Rwork0.1721 ---
obs0.1741 34209 80.6 %-
Displacement parametersBiso max: 78.56 Å2 / Biso mean: 23.097 Å2 / Biso min: 5.85 Å2
Baniso -1Baniso -2Baniso -3
1--0.9948 Å20 Å20.3439 Å2
2--0.7496 Å20 Å2
3---0.2452 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: final / Resolution: 1.697→57.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2798 0 47 347 3192
Biso mean--32.92 32.37 -
Num. residues----342
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1281SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes2HARMONIC2
X-RAY DIFFRACTIONt_gen_planes916HARMONIC16
X-RAY DIFFRACTIONt_it5742HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion374SEMIHARMONIC5
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_contact5084SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5748HARMONIC20.013
X-RAY DIFFRACTIONt_angle_deg10407HARMONIC21.12
X-RAY DIFFRACTIONt_omega_torsion5.97
X-RAY DIFFRACTIONt_other_torsion15.8
LS refinement shellResolution: 1.7→1.72 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.277 30 4.38 %
Rwork0.2203 655 -
all0.2227 685 -
obs--42.14 %
Refinement TLS params.Method: refined / Origin x: -1.389 Å / Origin y: 3.8593 Å / Origin z: 37.9985 Å
111213212223313233
T-0.0117 Å2-0.0012 Å20.0168 Å2--0.0077 Å2-0.0094 Å2--0.0063 Å2
L0.2476 °2-0.1826 °20.1925 °2-0.0256 °2-0.1333 °2--0.4502 °2
S-0.0251 Å °-0.02 Å °0.0383 Å °0.0254 Å °0.0325 Å °0.0048 Å °-0.0272 Å °-0.0117 Å °-0.0074 Å °
Refinement TLS groupSelection details: { A|11 - A|356 }

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