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- PDB-6g9m: Fragment-based discovery of a highly potent, orally bioavailable ... -

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Basic information

Entry
Database: PDB / ID: 6g9m
TitleFragment-based discovery of a highly potent, orally bioavailable inhibitor which modulates the phosphorylation and catalytic activity of ERK1/2
ComponentsMitogen-activated protein kinase 1
KeywordsSIGNALING PROTEIN / Erk2 Kinase inhibitor
Function / homology
Function and homology information


phospho-PLA2 pathway / Signaling by MAPK mutants / Suppression of apoptosis / RAF-independent MAPK1/3 activation / 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 / Suppression of apoptosis / RAF-independent MAPK1/3 activation / 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 cytoskeleton organization / 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 / face development / Activation of the AP-1 family of transcription factors / androgen receptor signaling pathway / ERK/MAPK targets / Recycling pathway of L1 / RUNX2 regulates osteoblast differentiation / pseudopodium / progesterone receptor signaling pathway / positive regulation of telomere capping / MAPK1 (ERK2) activation / negative regulation of cell differentiation / Bergmann glial cell differentiation / 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 / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / MAP kinase activity / phosphatase binding / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Nuclear events stimulated by ALK signaling in cancer / stress-activated MAPK cascade / Schwann cell development / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of telomerase activity / ERK1 and ERK2 cascade / cellular response to cadmium ion / cellular response to amino acid starvation / positive regulation of telomere maintenance via telomerase / myelination / NPAS4 regulates expression of target genes / 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 / response to nicotine / positive regulation of peptidyl-threonine phosphorylation / Regulation of PTEN gene transcription / Signal transduction by L1 / long-term synaptic potentiation / caveola / 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 / B cell receptor signaling pathway / Spry regulation of FGF signaling / peptidyl-threonine phosphorylation / Signaling by high-kinase activity BRAF mutants / regulation of protein stability / MAP2K and MAPK activation / 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-ESW / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.86 Å
AuthorsO'Reilly, M.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.
Authors: Heightman, T.D. / Berdini, V. / Braithwaite, H. / Buck, I.M. / Cassidy, M. / Castro, J. / Courtin, A. / Day, J.E.H. / East, C. / Fazal, L. / Graham, B. / Griffiths-Jones, C.M. / Lyons, J.F. ...Authors: Heightman, T.D. / Berdini, V. / Braithwaite, H. / Buck, I.M. / Cassidy, M. / Castro, J. / Courtin, A. / Day, J.E.H. / East, C. / Fazal, L. / Graham, B. / Griffiths-Jones, C.M. / Lyons, J.F. / Martins, V. / Muench, S. / Munck, J.M. / Norton, D. / O'Reilly, M. / Palmer, N. / Pathuri, P. / Reader, M. / Rees, D.C. / Rich, S.J. / Richardson, C. / Saini, H. / Thompson, N.T. / 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
DepositionApr 11, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 30, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 13, 2018Group: Data collection / Database references / Category: citation / Item: _citation.title
Revision 1.2Jun 27, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)43,3605
Polymers42,5521
Non-polymers8084
Water8,665481
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry, non-phosphorylated protein
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area480 Å2
ΔGint-33 kcal/mol
Surface area16230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.808, 70.843, 60.375
Angle α, β, γ (deg.)90.00, 109.65, 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 BL21(DE3) (bacteria)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-ESW / 2-[5-[5-chloranyl-2-(oxan-4-ylamino)pyrimidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]-~{N}-(2-phenylpropan-2-yl)ethanamide


Mass: 520.023 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H30ClN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 481 / 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: 46.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 2M (NH4)2SO4 32% MPEG 2000 .02M Mercaptoethanol .1M pH=7.2 HEPES/NaOH

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54178 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Apr 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.86→30.06 Å / Num. obs: 31764 / % possible obs: 97.3 % / Redundancy: 2.8 % / Biso Wilson estimate: 26.89 Å2 / Rrim(I) all: 0.049 / Net I/σ(I): 15.1
Reflection shellResolution: 1.86→1.87 Å / Mean I/σ(I) obs: 1.3 / Num. unique obs: 436 / Rrim(I) all: 0.794 / % possible all: 89.7

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.86→28.92 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.934 / SU R Cruickshank DPI: 0.203 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.14 / SU Rfree Blow DPI: 0.132 / SU Rfree Cruickshank DPI: 0.125
RfactorNum. reflection% reflectionSelection details
Rfree0.206 1630 5.15 %RANDOM
Rwork0.157 ---
obs0.16 31658 97 %-
Displacement parametersBiso mean: 36.971 Å2
Baniso -1Baniso -2Baniso -3
1-1.0962 Å20 Å24.0155 Å2
2---1.1539 Å20 Å2
3---0.0577 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: 1 / Resolution: 1.86→28.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2774 0 62 481 3317
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0135754HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0810414HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1273SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes72HARMONIC2
X-RAY DIFFRACTIONt_gen_planes847HARMONIC16
X-RAY DIFFRACTIONt_it5748HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.31
X-RAY DIFFRACTIONt_other_torsion15.36
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion373SEMIHARMONIC5
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_contact6616SEMIHARMONIC4
LS refinement shellResolution: 1.86→1.92 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.3222 126 4.78 %
Rwork0.2402 2510 -
all0.244 2636 -
obs--87.91 %
Refinement TLS params.Method: refined / Origin x: -1.5115 Å / Origin y: 3.6013 Å / Origin z: 38.0279 Å
111213212223313233
T-0.0678 Å20.0212 Å2-0.0023 Å2--0.0958 Å2-0.0346 Å2---0.0921 Å2
L1.2715 °2-0.5795 °20.6625 °2-1.2146 °2-0.4966 °2--1.1532 °2
S-0.1579 Å °-0.153 Å °0.1033 Å °0.2385 Å °0.1036 Å °-0.1234 Å °-0.1482 Å °-0.1036 Å °0.0543 Å °
Refinement TLS groupSelection details: { A|11 - A|356 }

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