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- PDB-7nr5: Discovery of ASTX029, a clinical candidate which modulates the ph... -

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Entry
Database: PDB / ID: 7nr5
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 / signal transduction / MAP kinase / ATP-binding protein
Function / homology
Function and homology information


phospho-PLA2 pathway / Suppression of apoptosis / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / caveolin-mediated endocytosis / cardiac neural crest cell development involved in heart development / cytosine metabolic process / response to epidermal growth factor ...phospho-PLA2 pathway / Suppression of apoptosis / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / caveolin-mediated endocytosis / cardiac neural crest cell development involved in heart development / 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 / regulation of cellular pH / outer ear morphogenesis / 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 / pseudopodium / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / androgen receptor signaling pathway / regulation of cytoskeleton organization / face development / : / 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 / Transcriptional and post-translational regulation of MITF-M expression and activity / mitogen-activated protein kinase / RHO GTPases Activate WASPs and WAVEs / phosphatase binding / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / 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 / cellular response to cadmium ion / NPAS4 regulates expression of target genes / myelination / cellular response to amino acid starvation / ERK1 and ERK2 cascade / 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 / Signaling by high-kinase activity BRAF mutants / Spry regulation of FGF signaling / 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-UOH / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.766 Å
AuthorsO'Reilly, M. / Cleasby, A.
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 3, 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

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,5176
Polymers42,5521
Non-polymers9655
Water6,341352
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area630 Å2
ΔGint-44 kcal/mol
Surface area16490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.903, 70.937, 60.445
Angle α, β, γ (deg.)90.000, 110.170, 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-Gold(DE3)pLysS AG' (bacteria)
Strain (production host): BL21(DE3)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-UOH / (2~{R})-2-[5-[5-chloranyl-2-[(2-methyl-1,2,3-triazol-4-yl)amino]pyrimidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]-~{N}-[(1~{S})-1-(3-fluoranyl-5-methoxy-phenyl)-2-oxidanyl-ethyl]propanamide


Mass: 580.998 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H26ClFN8O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 352 / 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: 46.82 %
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 EIGER R 1M / Detector: PIXEL / Date: May 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.766→44.31 Å / Num. obs: 31797 / % possible obs: 83.4 % / Redundancy: 2.6 % / Rrim(I) all: 0.048 / Net I/σ(I): 10.1
Reflection shellResolution: 1.766→1.8 Å / Num. unique obs: 1732 / Rrim(I) all: 0.843 / % possible all: 94.3

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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: 1.766→30.07 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.922 / SU R Cruickshank DPI: 0.214 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.143 / SU Rfree Blow DPI: 0.136 / SU Rfree Cruickshank DPI: 0.133
RfactorNum. reflection% reflectionSelection details
Rfree0.2226 1620 5.1 %RANDOM
Rwork0.1736 ---
obs0.1761 31784 83.4 %-
Displacement parametersBiso max: 122.99 Å2 / Biso mean: 27.647 Å2 / Biso min: 9.61 Å2
Baniso -1Baniso -2Baniso -3
1--0.8294 Å20 Å22.0325 Å2
2--0.2777 Å20 Å2
3---0.5517 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: final / Resolution: 1.766→30.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2793 0 87 352 3232
Biso mean--40.63 35.51 -
Num. residues----342
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1289SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes928HARMONIC16
X-RAY DIFFRACTIONt_it5807HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion376SEMIHARMONIC5
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_contact5070SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5813HARMONIC20.013
X-RAY DIFFRACTIONt_angle_deg10520HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion6.28
X-RAY DIFFRACTIONt_other_torsion16.55
LS refinement shellResolution: 1.77→1.78 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3078 35 5.5 %
Rwork0.2673 601 -
all0.2693 636 -
obs--92.72 %
Refinement TLS params.Method: refined / Origin x: -1.7337 Å / Origin y: 3.5767 Å / Origin z: 38.0486 Å
111213212223313233
T-0.0153 Å20.0119 Å20.0111 Å2--0.024 Å2-0.025 Å2--0.0204 Å2
L0.1573 °2-0.1444 °20.2632 °2-0.2873 °2-0.1366 °2--0.5105 °2
S-0.0649 Å °-0.0209 Å °0.0824 Å °0.0262 Å °0.0474 Å °-0.0698 Å °0.0023 Å °-0.0539 Å °0.0174 Å °
Refinement TLS groupSelection details: { A|11 - A|365 }

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