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- PDB-6dcg: Discovery of MK-8353: An Orally Bioavailable Dual Mechanism ERK I... -

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Basic information

Entry
Database: PDB / ID: 6dcg
TitleDiscovery of MK-8353: An Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE INHIBITOR / KINASE SELECTIVITY / TRANSFERASE / SERINE/ THREONINE-PROTEIN KINASE / MAP KINASE / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


phospho-PLA2 pathway / RAF-independent MAPK1/3 activation / MAPK1 (ERK2) activation / Signaling by NODAL / Frs2-mediated activation / ERK/MAPK targets / ERKs are inactivated / Activation of the AP-1 family of transcription factors / Transcriptional and post-translational regulation of MITF-M expression and activity / Negative feedback regulation of MAPK pathway ...phospho-PLA2 pathway / RAF-independent MAPK1/3 activation / MAPK1 (ERK2) activation / Signaling by NODAL / Frs2-mediated activation / ERK/MAPK targets / ERKs are inactivated / Activation of the AP-1 family of transcription factors / Transcriptional and post-translational regulation of MITF-M expression and activity / Negative feedback regulation of MAPK pathway / Gastrin-CREB signalling pathway via PKC and MAPK / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / IFNG signaling activates MAPKs / Golgi Cisternae Pericentriolar Stack Reorganization / RHO GTPases Activate WASPs and WAVEs / Estrogen-stimulated signaling through PRKCZ / Growth hormone receptor signaling / Spry regulation of FGF signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Oxidative Stress Induced Senescence / Senescence-Associated Secretory Phenotype (SASP) / Oncogene Induced Senescence / Regulation of actin dynamics for phagocytic cup formation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Signal attenuation / NCAM signaling for neurite out-growth / Negative regulation of FGFR1 signaling / Negative regulation of FGFR3 signaling / Negative regulation of FGFR4 signaling / Regulation of the apoptosome activity / Signaling by Activin / Negative regulation of FGFR2 signaling / Signal transduction by L1 / RHO GTPases Activate NADPH Oxidases / Negative regulation of MAPK pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interferon gamma signaling / FCERI mediated MAPK activation / Regulation of HSF1-mediated heat shock response / diadenosine tetraphosphate biosynthetic process / MAP2K and MAPK activation / neural crest cell development / Recycling pathway of L1 / cellular response to toxic substance / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / mitogen-activated protein kinase kinase kinase binding / cellular response to methionine / response to epidermal growth factor / positive regulation of macrophage proliferation / response to alcohol / regulation of cellular pH / outer ear morphogenesis / regulation of Golgi inheritance / labyrinthine layer blood vessel development / RAF/MAP kinase cascade / Thrombin signalling through proteinase activated receptors (PARs) / ERBB signaling pathway / Neutrophil degranulation / mammary gland epithelial cell proliferation / trachea formation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / cellular response to insulin-like growth factor stimulus / ERBB2-ERBB3 signaling pathway / positive regulation of macrophage chemotaxis / regulation of cytoskeleton organization / response to exogenous dsRNA / face development / lung morphogenesis / positive regulation of telomere maintenance / response to testosterone / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / thyroid gland development / steroid hormone receptor signaling pathway / decidualization / MAP kinase activity / negative regulation of cell differentiation / regulation of ossification / JUN kinase activity / mitogen-activated protein kinase / phosphatase binding / Schwann cell development / progesterone receptor signaling pathway / stress-activated MAPK cascade / estrous cycle / positive regulation of cardiac muscle cell proliferation / cellular response to platelet-derived growth factor stimulus / cellular response to cAMP / sensory perception of pain / dendrite cytoplasm / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / ERK1 and ERK2 cascade / cellular response to epidermal growth factor stimulus
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-G67 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 Å
AuthorsBoga, S.B. / Deng, Y. / Zhu, L. / Nan, Y. / Cooper, A. / Shipps Jr., G.W. / Doll, R. / Shih, N. / Zhu, H. / Sun, R. ...Boga, S.B. / Deng, Y. / Zhu, L. / Nan, Y. / Cooper, A. / Shipps Jr., G.W. / Doll, R. / Shih, N. / Zhu, H. / Sun, R. / Wang, T. / Paliwal, S. / Tsui, H. / Gao, X. / Yao, X. / Desai, J. / Wang, J. / Alhassan, A.B. / Kelly, J. / Patel, M. / Muppalla, K. / Gudipati, S. / Zhang, L. / Buevich, A. / Hesk, D. / Carr, D. / Dayananth, P. / Mei, H. / Cox, K. / Sherborne, B. / Hruza, A.W. / Xiao, L. / Jin, W. / Long, B. / Liu, G. / Taylor, S.A. / Kirschmeier, P. / Windsor, W.T. / Bishop, R. / Samatar, A.A.
CitationJournal: ACS Med Chem Lett / Year: 2018
Title: MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology.
Authors: Boga, S.B. / Deng, Y. / Zhu, L. / Nan, Y. / Cooper, A.B. / Shipps Jr., G.W. / Doll, R. / Shih, N.Y. / Zhu, H. / Sun, R. / Wang, T. / Paliwal, S. / Tsui, H.C. / Gao, X. / Yao, X. / Desai, J. ...Authors: Boga, S.B. / Deng, Y. / Zhu, L. / Nan, Y. / Cooper, A.B. / Shipps Jr., G.W. / Doll, R. / Shih, N.Y. / Zhu, H. / Sun, R. / Wang, T. / Paliwal, S. / Tsui, H.C. / Gao, X. / Yao, X. / Desai, J. / Wang, J. / Alhassan, A.B. / Kelly, J. / Patel, M. / Muppalla, K. / Gudipati, S. / Zhang, L.K. / Buevich, A. / Hesk, D. / Carr, D. / Dayananth, P. / Black, S. / Mei, H. / Cox, K. / Sherborne, B. / Hruza, A.W. / Xiao, L. / Jin, W. / Long, B. / Liu, G. / Taylor, S.A. / Kirschmeier, P. / Windsor, W.T. / Bishop, R. / Samatar, A.A.
History
DepositionMay 6, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 8, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)43,2464
Polymers42,3621
Non-polymers8843
Water4,486249
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)70.018, 91.173, 63.051
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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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: 42361.703 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Mapk1, Erk2, Mapk, Prkm1 / Production host: Escherichia coli (E. coli)
References: UniProt: P63086, 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-G67 / (3S)-3-(methylsulfanyl)-1-(2-{4-[4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]-3,6-dihydropyridin-1(2H)-yl}-2-oxoethyl)-N-(3-{6-[(propan-2-yl)oxy]pyridin-3-yl}-1H-indazol-5-yl)pyrrolidine-3-carboxamide


Mass: 691.845 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H41N9O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 249 / 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: 2.38 Å3/Da / Density % sol: 48.22 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: 0.1M MES, PH 6.4, 2.0M AMMONIUM SULFATE, 5% PEG 400, 0.5% DMSO, 1% GLYEROL, 0.0005M OLOMOUCINE, 13 DAY SOAK WITH NEW COMPOUND AT 500 MICROMOLAR CONCENTRATION

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: A1 / Wavelength: 0.9777 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: May 6, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9777 Å / Relative weight: 1
ReflectionResolution: 1.45→30 Å / Num. obs: 70144 / % possible obs: 97.1 % / Redundancy: 5.2 % / Biso Wilson estimate: 18.88 Å2 / Rmerge(I) obs: 0.048 / Net I/σ(I): 27.1
Reflection shellResolution: 1.45→1.48 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.564 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 3388 / % possible all: 94.7

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
DENZOdata reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ERK

1erk
PDB Unreleased entry


Resolution: 1.45→29.79 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.95 / SU R Cruickshank DPI: 0.065 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.061 / SU Rfree Blow DPI: 0.061 / SU Rfree Cruickshank DPI: 0.06
RfactorNum. reflection% reflectionSelection details
Rfree0.199 3509 5 %RANDOM
Rwork0.177 ---
obs0.178 70111 97.1 %-
Displacement parametersBiso mean: 25.46 Å2
Baniso -1Baniso -2Baniso -3
1--0.8149 Å20 Å20 Å2
2---0.2967 Å20 Å2
3---1.1115 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: 1 / Resolution: 1.45→29.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2667 0 60 249 2976
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015565HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0610063HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1233SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes68HARMONIC2
X-RAY DIFFRACTIONt_gen_planes847HARMONIC5
X-RAY DIFFRACTIONt_it5565HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.92
X-RAY DIFFRACTIONt_other_torsion14.75
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion360SEMIHARMONIC5
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_contact6348SEMIHARMONIC4
LS refinement shellResolution: 1.45→1.49 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.249 273 5.45 %
Rwork0.213 4739 -
all0.215 5012 -
obs--95.27 %
Refinement TLS params.Method: refined / Origin x: 52.027 Å / Origin y: 19.0191 Å / Origin z: 19.8772 Å
111213212223313233
T-0.0492 Å20.0154 Å2-0.0113 Å2--0.0608 Å2-0.0024 Å2---0.0598 Å2
L1.0783 °2-0.4559 °2-0.5731 °2-0.5807 °20.1968 °2--0.8631 °2
S0.0538 Å °0.1637 Å °-0.0866 Å °-0.0661 Å °-0.0848 Å °0.0871 Å °-0.0398 Å °-0.1087 Å °0.031 Å °
Refinement TLS groupSelection details: { A|* }

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