[English] 日本語
Yorodumi
- PDB-6n3l: Identification of novel, potent and selective GCN2 inhibitors as ... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 6n3l
TitleIdentification of novel, potent and selective GCN2 inhibitors as first-in-class anti-tumor agents
ComponentseIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2
Keywordstransferase/transferase inhibitor / GCN2 / Kinase / Inhibitor / Anti-tumor / transferase-transferase inhibitor complex
Function / homology
Function and homology information


positive regulation of translational initiation in response to starvation / negative regulation of cytoplasmic translational initiation in response to stress / negative regulation of CREB transcription factor activity / regulation of translational initiation by eIF2 alpha phosphorylation / eiF2alpha phosphorylation in response to endoplasmic reticulum stress / GCN2-mediated signaling / eukaryotic translation initiation factor 2alpha kinase activity / negative regulation of translational initiation in response to stress / negative regulation by host of viral genome replication / regulation of feeding behavior ...positive regulation of translational initiation in response to starvation / negative regulation of cytoplasmic translational initiation in response to stress / negative regulation of CREB transcription factor activity / regulation of translational initiation by eIF2 alpha phosphorylation / eiF2alpha phosphorylation in response to endoplasmic reticulum stress / GCN2-mediated signaling / eukaryotic translation initiation factor 2alpha kinase activity / negative regulation of translational initiation in response to stress / negative regulation by host of viral genome replication / regulation of feeding behavior / positive regulation of adaptive immune response / T cell activation involved in immune response / regulation of translational initiation / cellular response to cold / neuron projection extension / Response of EIF2AK4 (GCN2) to amino acid deficiency / negative regulation of neuron differentiation / long-term memory / positive regulation of defense response to virus by host / negative regulation of translational initiation / cytosolic ribosome / cellular response to amino acid starvation / DNA damage checkpoint signaling / learning / positive regulation of long-term synaptic potentiation / cellular response to UV / defense response to virus / viral translation / protein autophosphorylation / adaptive immune response / tRNA binding / non-specific serine/threonine protein kinase / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
eIF-2-alpha kinase Gcn2 / Histidyl tRNA synthetase-related domain / Anticodon binding domain of tRNAs / RWD domain / RWD domain profile. / RWD / RWD domain / Class II Histidinyl-tRNA synthetase (HisRS)-like catalytic core domain / Histidyl-tRNA synthetase / : ...eIF-2-alpha kinase Gcn2 / Histidyl tRNA synthetase-related domain / Anticodon binding domain of tRNAs / RWD domain / RWD domain profile. / RWD / RWD domain / Class II Histidinyl-tRNA synthetase (HisRS)-like catalytic core domain / Histidyl-tRNA synthetase / : / Anticodon-binding domain superfamily / Ubiquitin-conjugating enzyme/RWD-like / Class II Aminoacyl-tRNA synthetase/Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL) / 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-KAV / eIF-2-alpha kinase GCN2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsHoffman, I.D. / Fujimoto, J. / Kurasawa, O. / Takagi, T. / Klein, M.G. / Kefala, G. / Ding, S.C. / Cary, D.R. / Mizojiri, R.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode.
Authors: Fujimoto, J. / Kurasawa, O. / Takagi, T. / Liu, X. / Banno, H. / Kojima, T. / Asano, Y. / Nakamura, A. / Nambu, T. / Hata, A. / Ishii, T. / Sameshima, T. / Debori, Y. / Miyamoto, M. / Klein, ...Authors: Fujimoto, J. / Kurasawa, O. / Takagi, T. / Liu, X. / Banno, H. / Kojima, T. / Asano, Y. / Nakamura, A. / Nambu, T. / Hata, A. / Ishii, T. / Sameshima, T. / Debori, Y. / Miyamoto, M. / Klein, M.G. / Tjhen, R. / Sang, B.C. / Levin, I. / Lane, S.W. / Snell, G.P. / Li, K. / Kefala, G. / Hoffman, I.D. / Ding, S.C. / Cary, D.R. / Mizojiri, R.
History
DepositionNov 15, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: eIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2
B: eIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,6384
Polymers75,7012
Non-polymers9372
Water86548
1
A: eIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3192
Polymers37,8511
Non-polymers4681
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: eIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3192
Polymers37,8511
Non-polymers4681
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)83.886, 122.233, 120.674
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: PRO / End label comp-ID: PRO / Refine code: _ / Auth seq-ID: 584 - 1002 / Label seq-ID: 24 - 319

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

-
Components

#1: Protein eIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2 / Eukaryotic translation initiation factor 2-alpha kinase 4 / GCN2-like protein


Mass: 37850.621 Da / Num. of mol.: 2
Mutation: D848N, T899A, T904A, K807A,D848N, T899A, T904A, K807A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2AK4, GCN2, KIAA1338 / Cell line (production host): Sf9 / Production host: unidentified baculovirus
References: UniProt: Q9P2K8, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-KAV / N-{6-[(1-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1H-benzimidazol-5-yl)oxy]pyrimidin-4-yl}cyclopropanecarboxamide


Mass: 468.431 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H19F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 48 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 2.22 Å3/Da / Density % sol: 39.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 100 mM Tris 8.5, 24% PEG3350, 450 mM NaFormate, 1% hexanediol

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97648 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 24, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97648 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 36200 / % possible obs: 99.5 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.117 / Rpim(I) all: 0.071 / Rrim(I) all: 0.133 / Χ2: 1.015 / Net I/σ(I): 8 / Num. measured all: 132879
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allΧ2% possible allRrim(I) all
2.6-2.643.20.8617250.660.5561.08496.5
2.64-2.693.30.83417860.6570.5341.10497.60.993
2.69-2.743.50.74117820.7110.4620.89999.20.875
2.74-2.83.60.72418120.6840.4430.96699.50.85
2.8-2.863.70.59918010.8230.3590.96699.70.699
2.86-2.933.80.49618100.8920.2960.96799.90.578
2.93-33.80.41517960.920.2471.00899.90.484
3-3.083.80.36618100.9230.2180.97699.90.426
3.08-3.173.80.29118290.9380.1741.00599.90.339
3.17-3.283.80.25417870.9440.1521.07599.80.296
3.28-3.393.80.20418200.9580.1231.05499.90.238
3.39-3.533.70.16718300.9720.1021.08599.80.196
3.53-3.693.70.14218030.9790.0881.16199.40.167
3.69-3.883.70.10918130.9840.0671.06599.80.128
3.88-4.133.80.08418260.9940.050.9731000.098
4.13-4.453.80.07318080.9930.0440.9961000.086
4.45-4.893.70.06718460.9930.0411.0041000.078
4.89-5.63.70.0618260.9960.0360.9841000.07
5.6-7.053.60.0518340.9960.0310.97199.90.06
7.05-503.80.03318560.9970.020.98299.10.039

-
Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.61→25 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.904 / SU B: 37.065 / SU ML: 0.34 / SU R Cruickshank DPI: 0.8171 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.817 / ESU R Free: 0.364
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2897 960 5.1 %RANDOM
Rwork0.2228 ---
obs0.2261 17799 97.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 181.19 Å2 / Biso mean: 59.547 Å2 / Biso min: 32.49 Å2
Baniso -1Baniso -2Baniso -3
1-1.76 Å20 Å20 Å2
2--0.49 Å20 Å2
3----2.26 Å2
Refinement stepCycle: final / Resolution: 2.61→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3802 0 68 48 3918
Biso mean--45.95 48.89 -
Num. residues----458
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0133973
X-RAY DIFFRACTIONr_bond_other_d0.0020.0173682
X-RAY DIFFRACTIONr_angle_refined_deg1.6091.6685366
X-RAY DIFFRACTIONr_angle_other_deg1.1921.5778499
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.8725447
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.88121.121232
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.34515692
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8151533
X-RAY DIFFRACTIONr_chiral_restr0.0720.2491
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024327
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02890
Refine LS restraints NCS

Ens-ID: 1 / Number: 7259 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.1 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.611→2.678 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.52 47 -
Rwork0.376 962 -
all-1009 -
obs--72.85 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.23742.1488-0.35033.1848-0.30163.2450.133-0.10150.19850.347-0.01570.2291-0.63010.1426-0.11730.4234-0.00610.01390.0156-0.01030.023321.2585140.03491.4619
23.92572.2484-0.0262.4819-1.13471.9410.00660.0630.24040.00720.1260.1951-0.0155-0.2715-0.13260.26440.0143-0.0120.09670.02450.024824.5619143.6722-31.6506
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A584 - 2501
2X-RAY DIFFRACTION2B584 - 2501

+
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