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

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Basic information

Entry
Database: PDB / ID: 6gdm
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 / interleukin-34-mediated signaling 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 ...phospho-PLA2 pathway / interleukin-34-mediated signaling 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 / Signaling by NODAL / ERKs are inactivated / Signaling by MAP2K mutants / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / Regulation of the apoptosome activity / positive regulation of macrophage proliferation / regulation of cellular pH / outer ear morphogenesis / Signaling by LTK in cancer / regulation of Golgi inheritance / positive regulation of peptidyl-threonine phosphorylation / 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 / IFNG signaling activates MAPKs / regulation of stress-activated MAPK cascade / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / positive regulation of macrophage chemotaxis / Activation of the AP-1 family of transcription factors / regulation of cytoskeleton organization / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / response to exogenous dsRNA / MAPK1 (ERK2) activation / lung morphogenesis / face development / pseudopodium / Bergmann glial cell differentiation / positive regulation of telomere maintenance / Recycling pathway of L1 / thyroid gland development / Advanced glycosylation endproduct receptor signaling / peptidyl-threonine phosphorylation / MAP kinase activity / regulation of ossification / negative regulation of cell differentiation / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / mitogen-activated protein kinase / RHO GTPases Activate WASPs and WAVEs / Signal attenuation / phosphatase binding / Growth hormone receptor signaling / Schwann cell development / Estrogen-stimulated signaling through PRKCZ / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / NPAS4 regulates expression of target genes / ERK1 and ERK2 cascade / phosphotyrosine residue binding / myelination / Transcriptional and post-translational regulation of MITF-M expression and activity / NCAM signaling for neurite out-growth / RNA polymerase II CTD heptapeptide repeat kinase activity / insulin-like growth factor receptor signaling pathway / ESR-mediated signaling / lipopolysaccharide-mediated signaling pathway / cellular response to amino acid starvation / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / B cell receptor signaling pathway / response to nicotine / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / positive regulation of cholesterol biosynthetic process / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / Oncogene Induced Senescence / regulation of protein stability / caveola / Regulation of actin dynamics for phagocytic cup formation / epidermal growth factor receptor signaling pathway / long-term synaptic potentiation / chemotaxis / Interferon gamma signaling
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-F3Z / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.91 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 24, 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
Revision 1.3Nov 13, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)43,6385
Polymers42,7801
Non-polymers8584
Water7,098394
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry, non-phosphorylated kinase
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area560 Å2
ΔGint-31 kcal/mol
Surface area16810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.722, 70.690, 60.615
Angle α, β, γ (deg.)90.00, 109.45, 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: 42780.277 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.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-F3Z / (3~{R})-1-[2-oxidanylidene-2-[4-(4-pyrimidin-2-ylphenyl)piperazin-1-yl]ethyl]-~{N}-(3-pyridin-4-yl-1~{H}-indazol-5-yl)pyrrolidine-3-carboxamide


Mass: 587.674 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H33N9O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 394 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.3 Å3/Da / Density % sol: 46.54 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 35.0%w/v MPEG 2000, 0.2M (NH4)2SO4, 0.1M HEPES/NaOHpH=7.2, 0.02M Mercaptoethanol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Apr 10, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.91→57.156 Å / Num. obs: 30330 / % possible obs: 97.7 % / Redundancy: 2.7 % / Rrim(I) all: 0.051 / Net I/σ(I): 14
Reflection shellResolution: 1.91→1.97 Å / Mean I/σ(I) obs: 1.9 / Num. unique obs: 689 / Rrim(I) all: 0.483 / % possible all: 83.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.91→27.47 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.918 / SU B: 8.033 / SU ML: 0.125 / Cross valid method: THROUGHOUT / ESU R: 0.168 / ESU R Free: 0.163 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24265 1527 5.2 %RANDOM
Rwork0.18204 ---
obs0.18515 28055 97.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 33.486 Å2
Baniso -1Baniso -2Baniso -3
1--0.93 Å2-0 Å20.02 Å2
2--0.84 Å2-0 Å2
3---0.07 Å2
Refinement stepCycle: 1 / Resolution: 1.91→27.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2826 0 58 394 3278
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0152975
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172693
X-RAY DIFFRACTIONr_angle_refined_deg1.4271.7684032
X-RAY DIFFRACTIONr_angle_other_deg0.4821.7286323
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5515349
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.08221.125144
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.63716.461503
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1511519
X-RAY DIFFRACTIONr_chiral_restr0.0740.2379
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0213258
X-RAY DIFFRACTIONr_gen_planes_other00.02542
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.0694.0731384
X-RAY DIFFRACTIONr_mcbond_other2.0574.0721384
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.7074.8111591
X-RAY DIFFRACTIONr_scbond_other2.7064.8131592
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.58523.0233386
X-RAY DIFFRACTIONr_long_range_B_other5.54222.573339
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.907→1.956 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 83 -
Rwork0.304 1722 -
obs--80.62 %
Refinement TLS params.Method: refined / Origin x: -1.1017 Å / Origin y: 3.5031 Å / Origin z: 38.4725 Å
111213212223313233
T0.0583 Å20.0069 Å20.0063 Å2-0.044 Å2-0.0249 Å2--0.0184 Å2
L2.0737 °2-0.5836 °20.741 °2-1.0172 °2-0.46 °2--1.8234 °2
S-0.0761 Å °-0.2647 Å °0.1751 Å °0.2261 Å °0.0677 Å °-0.009 Å °-0.1839 Å °-0.0947 Å °0.0084 Å °

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