[English] 日本語
Yorodumi
- PDB-6g9j: Fragment-based discovery of a highly potent, orally bioavailable ... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 6g9j
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 / 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 ...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 / 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 / outer ear morphogenesis / regulation of cellular pH / 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 / regulation of cytoskeleton organization / Activation of the AP-1 family of transcription factors / face development / ERK/MAPK targets / androgen receptor signaling pathway / RUNX2 regulates osteoblast differentiation / pseudopodium / : / 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 / MAP kinase activity / RHO GTPases Activate NADPH Oxidases / Regulation of HSF1-mediated heat shock response / regulation of ossification / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate WASPs and WAVEs / mitogen-activated protein kinase / phosphatase binding / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Transcriptional and post-translational regulation of MITF-M expression and activity / progesterone receptor signaling pathway / Schwann cell development / Nuclear events stimulated by ALK signaling in cancer / Growth hormone receptor signaling / stress-activated MAPK cascade / lipopolysaccharide-mediated signaling pathway / positive regulation of telomere maintenance via telomerase / NPAS4 regulates expression of target genes / cellular response to cadmium ion / myelination / ERK1 and ERK2 cascade / cellular response to amino acid starvation / phosphotyrosine residue binding / 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 / FCERI mediated MAPK activation / long-term synaptic potentiation / response to nicotine / Negative regulation of FGFR3 signaling / FCGR3A-mediated phagocytosis / peptidyl-threonine phosphorylation / B cell receptor signaling pathway / Negative regulation of FGFR2 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / 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 / caveola / Oncogene Induced Senescence
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. ...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-ERK / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.98 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 10, 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 20, 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

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


Theoretical massNumber of molelcules
Total (without water)43,4024
Polymers42,7041
Non-polymers6983
Water7,260403
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry, non-phosphorylated enzyme
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area360 Å2
ΔGint-25 kcal/mol
Surface area16530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.842, 70.258, 60.577
Angle α, β, γ (deg.)90.00, 109.90, 90.00
Int Tables number4
Space group name H-MP1211

-
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: 42704.152 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-ERK / 2-[5-[5-chloranyl-2-(oxan-4-ylamino)pyrimidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]-~{N}-[(1~{R})-1-phenylethyl]ethanamide


Mass: 505.996 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H28ClN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 403 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.29 Å3/Da / Density % sol: 46.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 0.3M (NH4)2SO4, 32.0%w/v MPEG 2000, 0.1M HEPES/NaOHpH=7.2, 0.02M Mercaptoethanol

-
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: Jun 24, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.98→28.34 Å / Num. obs: 25455 / % possible obs: 94.2 % / Redundancy: 3.1 % / Biso Wilson estimate: 28.49 Å2 / Rrim(I) all: 0.082 / Net I/σ(I): 9.6
Reflection shellResolution: 1.98→2.03 Å / Num. unique obs: 1958 / Rrim(I) all: 0.998 / % possible all: 87.5

-
Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.98→28.34 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.929 / SU R Cruickshank DPI: 0.731 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.186 / SU Rfree Blow DPI: 0.16 / SU Rfree Cruickshank DPI: 0.154
RfactorNum. reflection% reflectionSelection details
Rfree0.212 1321 5.22 %RANDOM
Rwork0.159 ---
obs0.162 25287 94 %-
Displacement parametersBiso mean: 38.051 Å2
Baniso -1Baniso -2Baniso -3
1-0.7252 Å20 Å23.5627 Å2
2--0.8709 Å20 Å2
3----1.5961 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: 1 / Resolution: 1.98→28.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2815 0 76 403 3294
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0125851HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.110573HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1302SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes74HARMONIC2
X-RAY DIFFRACTIONt_gen_planes862HARMONIC16
X-RAY DIFFRACTIONt_it5833HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.41
X-RAY DIFFRACTIONt_other_torsion15.91
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion381SEMIHARMONIC5
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_contact7033SEMIHARMONIC4
LS refinement shellResolution: 1.98→2.06 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.2818 129 4.86 %
Rwork0.2113 2524 -
all0.2147 2653 -
obs--87.89 %
Refinement TLS params.Method: refined / Origin x: -1.5067 Å / Origin y: 3.5624 Å / Origin z: 38.4584 Å
111213212223313233
T-0.0655 Å20.0099 Å20.0024 Å2--0.0796 Å2-0.0383 Å2---0.067 Å2
L1.0986 °2-0.3695 °20.5682 °2-0.9057 °2-0.2978 °2--1.1805 °2
S-0.1027 Å °-0.1265 Å °0.1076 Å °0.1751 Å °0.0785 Å °-0.0971 Å °-0.1181 Å °-0.0662 Å °0.0242 Å °
Refinement TLS groupSelection details: { A|8 - A|365 }

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more