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- PDB-7nr3: Discovery of ASTX029, a clinical candidate which modulates the ph... -

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Entry
Database: PDB / ID: 7nr3
TitleDiscovery of ASTX029, a clinical candidate which modulates the phosphorylation and catalytic activity of ERK1/2
ComponentsMitogen-activated protein kinase 1
KeywordsSIGNALING PROTEIN / Serine-threonine kinase / protein kinase / signal transduction / MAP kinase
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 / cytosine metabolic process / ERKs are inactivated ...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 / cytosine metabolic process / ERKs are inactivated / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / regulation of cellular pH / positive regulation of macrophage proliferation / outer ear morphogenesis / Regulation of the apoptosome activity / 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 / androgen receptor signaling pathway / pseudopodium / RUNX2 regulates osteoblast differentiation / Recycling pathway of L1 / progesterone receptor signaling pathway / 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 mediated signaling pathway / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / 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 / Nuclear events stimulated by ALK signaling in cancer / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Schwann cell development / stress-activated MAPK cascade / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of telomerase activity / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / ERK1 and ERK2 cascade / NPAS4 regulates expression of target genes / 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 / FCGR3A-mediated phagocytosis / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / B cell receptor signaling pathway / peptidyl-threonine phosphorylation / Spry regulation of FGF signaling / response to nicotine / Signaling by high-kinase activity BRAF mutants / 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. / 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. ...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-UO5 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.897 Å
AuthorsO'Reilly, M.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.
Authors: Heightman, T.D. / Berdini, V. / Bevan, L. / Buck, I.M. / Carr, M.G. / Courtin, A. / Coyle, J.E. / Day, J.E.H. / East, C. / Fazal, L. / Griffiths-Jones, C.M. / Howard, S. / Kucia-Tran, J. / ...Authors: Heightman, T.D. / Berdini, V. / Bevan, L. / Buck, I.M. / Carr, M.G. / Courtin, A. / Coyle, J.E. / Day, J.E.H. / East, C. / Fazal, L. / Griffiths-Jones, C.M. / Howard, S. / Kucia-Tran, J. / Martins, V. / Muench, S. / Munck, J.M. / Norton, D. / O'Reilly, M. / Palmer, N. / Pathuri, P. / Peakman, T.M. / Reader, M. / Rees, D.C. / Rich, S.J. / Shah, A. / Wallis, N.G. / Walton, H. / Wilsher, N.E. / Woolford, A.J. / Cooke, M. / Cousin, D. / Onions, S. / Shannon, J. / Watts, J. / Murray, C.W.
History
DepositionMar 2, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2764
Polymers42,5521
Non-polymers7243
Water6,503361
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area290 Å2
ΔGint-18 kcal/mol
Surface area16100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.835, 70.700, 60.354
Angle α, β, γ (deg.)90.000, 109.400, 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 (E. coli) / Strain (production host): BL21(DE7)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-UO5 / 6-[5-chloranyl-2-(oxan-4-ylamino)pyrimidin-4-yl]-2-[2-oxidanylidene-2-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)ethyl]-3~{H}-isoindol-1-one


Mass: 532.033 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H30ClN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 361 / 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: 2.31 Å3/Da / Density % sol: 46.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
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+ / Wavelength: 1.54178 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: May 6, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.897→46.06 Å / Num. obs: 29169 / % possible obs: 95.2 % / Redundancy: 3.4 % / Rrim(I) all: 0.051 / Net I/σ(I): 17.7
Reflection shellResolution: 1.897→1.9 Å / Num. unique obs: 85 / Rrim(I) all: 0.605 / % possible all: 65.2

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (19-MAR-2020)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.897→46.06 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.912 / SU R Cruickshank DPI: 0.28 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.167 / SU Rfree Blow DPI: 0.155 / SU Rfree Cruickshank DPI: 0.151
RfactorNum. reflection% reflectionSelection details
Rfree0.2364 1503 5.16 %RANDOM
Rwork0.1837 ---
obs0.1864 29100 94.7 %-
Displacement parametersBiso max: 104.93 Å2 / Biso mean: 32.662 Å2 / Biso min: 6.28 Å2
Baniso -1Baniso -2Baniso -3
1-1.0286 Å20 Å23.1476 Å2
2---3.8869 Å20 Å2
3---2.8584 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 1.897→46.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2757 0 78 361 3196
Biso mean--47.39 40.24 -
Num. residues----337
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1276SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes909HARMONIC16
X-RAY DIFFRACTIONt_it5719HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion369SEMIHARMONIC5
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_contact4875SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5725HARMONIC20.013
X-RAY DIFFRACTIONt_angle_deg10372HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion6.23
X-RAY DIFFRACTIONt_other_torsion16.58
LS refinement shellResolution: 1.9→1.92 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3721 25 4.3 %
Rwork0.3408 557 -
all0.3421 582 -
obs--57.41 %
Refinement TLS params.Method: refined / Origin x: -1.1831 Å / Origin y: 3.6888 Å / Origin z: 37.853 Å
111213212223313233
T-0.0058 Å20.0266 Å20.0002 Å2--0.038 Å2-0.0221 Å2--0.0431 Å2
L0.5147 °2-0.5873 °20.4128 °2-0.4728 °2-0.2777 °2--0.5593 °2
S-0.1425 Å °-0.0381 Å °0.0744 Å °0.0988 Å °0.1184 Å °-0.0814 Å °-0.0472 Å °-0.0924 Å °0.0241 Å °
Refinement TLS groupSelection details: { A|11 - A|365 }

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