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- PDB-4o6e: Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine Inhibitors... -

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Basic information

Entry
Database: PDB / ID: 4o6e
TitleDiscovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine Inhibitors of Erk2
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein Kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


phospho-PLA2 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 / Signaling by MAP2K mutants ...phospho-PLA2 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 / Signaling by MAP2K mutants / Signaling by NODAL / ERKs are inactivated / response to epidermal growth factor / 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 / labyrinthine layer blood vessel development / ERBB signaling pathway / mammary gland epithelial cell proliferation / trachea formation / Negative feedback regulation of MAPK pathway / positive regulation of peptidyl-threonine phosphorylation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / MAPK1 (ERK2) activation / 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 / face development / lung morphogenesis / positive regulation of telomere maintenance / Recycling pathway of L1 / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / thyroid gland development / steroid hormone receptor signaling pathway / Advanced glycosylation endproduct receptor signaling / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / negative regulation of cell differentiation / regulation of ossification / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate WASPs and WAVEs / JUN kinase activity / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / phosphatase binding / Schwann cell development / Growth hormone receptor signaling / progesterone receptor signaling pathway / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / NPAS4 regulates expression of target genes / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / Transcriptional and post-translational regulation of MITF-M expression and activity / NCAM signaling for neurite out-growth / ERK1 and ERK2 cascade / cellular response to amino acid starvation / insulin-like growth factor receptor signaling pathway / lipopolysaccharide-mediated signaling pathway / ESR-mediated signaling / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / response to nicotine / 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 / positive regulation of cholesterol biosynthetic process / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / regulation of protein stability / Oncogene Induced Senescence / caveola / Regulation of actin dynamics for phagocytic cup formation / long-term synaptic potentiation
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-2SH / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsYin, J. / Wang, W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2.
Authors: Blake, J.F. / Gaudino, J.J. / De Meese, J. / Mohr, P. / Chicarelli, M. / Tian, H. / Garrey, R. / Thomas, A. / Siedem, C.S. / Welch, M.B. / Kolakowski, G. / Kaus, R. / Burkard, M. / ...Authors: Blake, J.F. / Gaudino, J.J. / De Meese, J. / Mohr, P. / Chicarelli, M. / Tian, H. / Garrey, R. / Thomas, A. / Siedem, C.S. / Welch, M.B. / Kolakowski, G. / Kaus, R. / Burkard, M. / Martinson, M. / Chen, H. / Dean, B. / Dudley, D.A. / Gould, S.E. / Pacheco, P. / Shahidi-Latham, S. / Wang, W. / West, K. / Yin, J. / Moffat, J. / Schwarz, J.B.
History
DepositionDec 20, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 21, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 25, 2014Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)43,0972
Polymers42,6471
Non-polymers4501
Water3,531196
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.850, 65.766, 52.654
Angle α, β, γ (deg.)90.00, 95.00, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Mitogen-activated protein kinase 1 / MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform ...MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK / Mitogen-activated protein kinase 2 / MAP kinase 2 / MAPK 2


Mass: 42646.941 Da / Num. of mol.: 1 / Fragment: UNP residues 13-360
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)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-2SH / N-[(1S)-1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]-2-(tetrahydro-2H-pyran-4-ylamino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide


Mass: 449.906 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H25ClFN5O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 196 / 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: 1.89 Å3/Da / Density % sol: 35.09 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 10% PEG3350, 0.2 M proline, and 0.1 M HEPES pH7.5, in a 24-well Linbro plates incubated at 4 C, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 28, 2009
RadiationMonochromator: Asymmetric curved crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. all: 23261 / Num. obs: 23214 / % possible obs: 99.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Biso Wilson estimate: 27.41 Å2
Reflection shellResolution: 1.95→2.02 Å / % possible all: 98.6

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
BUSTER2.11.4refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→46.67 Å / Cor.coef. Fo:Fc: 0.9534 / Cor.coef. Fo:Fc free: 0.9373 / SU R Cruickshank DPI: 0.178 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2232 1211 5.22 %RANDOM
Rwork0.1805 ---
all0.2232 23261 --
obs0.1828 23192 99.47 %-
Displacement parametersBiso mean: 32.38 Å2
Baniso -1Baniso -2Baniso -3
1-0.2461 Å20 Å2-1.5848 Å2
2---0.7105 Å20 Å2
3---0.4644 Å2
Refine analyzeLuzzati coordinate error obs: 0.224 Å
Refinement stepCycle: LAST / Resolution: 1.95→46.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2676 0 31 196 2903
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012803HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.973797HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d990SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes73HARMONIC2
X-RAY DIFFRACTIONt_gen_planes395HARMONIC5
X-RAY DIFFRACTIONt_it2803HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.95
X-RAY DIFFRACTIONt_other_torsion17.59
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion359SEMIHARMONIC5
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_contact3279SEMIHARMONIC4
LS refinement shellResolution: 1.95→2.04 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2638 142 5.25 %
Rwork0.2093 2561 -
all0.2122 2703 -
obs--99.47 %
Refinement TLS params.Method: refined / Origin x: 8.7397 Å / Origin y: 0.8121 Å / Origin z: 8.2929 Å
111213212223313233
T0.0749 Å2-0.0018 Å20.0351 Å2-0.0971 Å20.0057 Å2--0.132 Å2
L1.0289 °2-0.0288 °20.3105 °2-0.8448 °2-0.2429 °2--0.9757 °2
S0.0933 Å °-0.0363 Å °0.0502 Å °0.0493 Å °-0.0679 Å °0.0033 Å °-0.0001 Å °0.0213 Å °-0.0254 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|13 - A|357 A|401 - A|401 A|501 - A|696 }A13 - 357
2X-RAY DIFFRACTION1{ A|13 - A|357 A|401 - A|401 A|501 - A|696 }A401
3X-RAY DIFFRACTION1{ A|13 - A|357 A|401 - A|401 A|501 - A|696 }A501 - 696

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