[English] 日本語
Yorodumi
- PDB-3qkl: Spirochromane Akt Inhibitors -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 3qkl
TitleSpirochromane Akt Inhibitors
Components
  • GSK-3 beta peptide
  • RAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase Domain / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / potassium channel activator activity / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / maintenance of protein location in mitochondrion / negative regulation of lymphocyte migration / cellular response to decreased oxygen levels / regulation of type B pancreatic cell development ...glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / potassium channel activator activity / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / maintenance of protein location in mitochondrion / negative regulation of lymphocyte migration / cellular response to decreased oxygen levels / regulation of type B pancreatic cell development / AKT-mediated inactivation of FOXO1A / maternal placenta development / Negative regulation of the PI3K/AKT network / negative regulation of long-chain fatty acid import across plasma membrane / establishment of protein localization to mitochondrion / negative regulation of fatty acid beta-oxidation / AKT phosphorylates targets in the nucleus / regulation of glycogen biosynthetic process / cellular response to oxidised low-density lipoprotein particle stimulus / negative regulation of cilium assembly / positive regulation of I-kappaB phosphorylation / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / response to fluid shear stress / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / MTOR signalling / fibroblast migration / interleukin-18-mediated signaling pathway / positive regulation of sodium ion transport / mammary gland epithelial cell differentiation / negative regulation of endopeptidase activity / negative regulation of protein serine/threonine kinase activity / RAB GEFs exchange GTP for GDP on RABs / positive regulation of glucose metabolic process / positive regulation of endodeoxyribonuclease activity / response to growth factor / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of protein localization to cell surface / protein serine/threonine kinase inhibitor activity / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / peripheral nervous system myelin maintenance / sphingosine-1-phosphate receptor signaling pathway / positive regulation of fibroblast migration / cell migration involved in sprouting angiogenesis / response to growth hormone / anoikis / glycogen biosynthetic process / AKT phosphorylates targets in the cytosol / labyrinthine layer blood vessel development / execution phase of apoptosis / response to food / response to UV-A / regulation of myelination / regulation of postsynapse organization / regulation of neuron projection development / KSRP (KHSRP) binds and destabilizes mRNA / Regulation of TP53 Activity through Association with Co-factors / mammalian oogenesis stage / negative regulation of macroautophagy / CTLA4 inhibitory signaling / negative regulation of cGAS/STING signaling pathway / activation-induced cell death of T cells / negative regulation of Notch signaling pathway / behavioral response to pain / non-canonical NF-kappaB signal transduction / negative regulation of release of cytochrome c from mitochondria / Constitutive Signaling by AKT1 E17K in Cancer / apoptotic mitochondrial changes / CD28 dependent PI3K/Akt signaling / phosphatidylinositol-3,4,5-trisphosphate binding / Regulation of localization of FOXO transcription factors / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of glycogen biosynthetic process / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / TOR signaling / Activation of BAD and translocation to mitochondria / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / positive regulation of fat cell differentiation / canonical NF-kappaB signal transduction / positive regulation of G1/S transition of mitotic cell cycle / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / eNOS activation / positive regulation of lipid biosynthetic process / Cyclin E associated events during G1/S transition / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Cyclin A:Cdk2-associated events at S phase entry / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / lipopolysaccharide-mediated signaling pathway / regulation of cell migration / negative regulation of protein ubiquitination / cellular response to epidermal growth factor stimulus / 14-3-3 protein binding / Regulation of TP53 Activity through Acetylation / positive regulation of TORC1 signaling / positive regulation of endothelial cell proliferation / striated muscle cell differentiation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1
Similarity search - Function
Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / PH domain profile. / Pleckstrin homology domain. ...Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily / 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-SMR / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsKallan, N.C. / Spencer, K.L. / Blake, J.F. / Xu, R. / Heizer, J. / Bencsik, J.R. / Mitchell, I.S. / Gloor, S.L. / Martinson, M. / Risom, T. ...Kallan, N.C. / Spencer, K.L. / Blake, J.F. / Xu, R. / Heizer, J. / Bencsik, J.R. / Mitchell, I.S. / Gloor, S.L. / Martinson, M. / Risom, T. / Gross, S.D. / Morales, T. / Vigers, G.P.A. / Brandhuber, B.J. / Skelton, N.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Discovery and SAR of spirochromane Akt inhibitors.
Authors: Kallan, N.C. / Spencer, K.L. / Blake, J.F. / Xu, R. / Heizer, J. / Bencsik, J.R. / Mitchell, I.S. / Gloor, S.L. / Martinson, M. / Risom, T. / Gross, S.D. / Morales, T.H. / Wu, W.I. / Vigers, ...Authors: Kallan, N.C. / Spencer, K.L. / Blake, J.F. / Xu, R. / Heizer, J. / Bencsik, J.R. / Mitchell, I.S. / Gloor, S.L. / Martinson, M. / Risom, T. / Gross, S.D. / Morales, T.H. / Wu, W.I. / Vigers, G.P. / Brandhuber, B.J. / Skelton, N.J.
History
DepositionFeb 1, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: RAC-alpha serine/threonine-protein kinase
C: GSK-3 beta peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,1473
Polymers40,5902
Non-polymers5571
Water4,270237
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1300 Å2
ΔGint-0 kcal/mol
Surface area15350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.741, 55.720, 91.019
Angle α, β, γ (deg.)90.00, 101.84, 90.00
Int Tables number4
Space group name H-MP1211

-
Components

#1: Protein RAC-alpha serine/threonine-protein kinase / Protein kinase B / PKB / Proto-oncogene c-Akt / RAC-PK-alpha


Mass: 39466.969 Da / Num. of mol.: 1 / Fragment: kinase domain / Mutation: S473D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT1, PKB, RAC / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P31749, non-specific serine/threonine protein kinase
#2: Protein/peptide GSK-3 beta peptide


Mass: 1123.220 Da / Num. of mol.: 1 / Source method: obtained synthetically
#3: Chemical ChemComp-SMR / N-{(2S)-3-[(3S)-8',9'-dihydro-1H,3'H-spiro[piperidine-3,7'-pyrano[3,2-e]indazol]-1-yl]-2-hydroxypropyl}-N-(2-ethoxyethyl)-2,6-dimethylbenzenesulfonamide


Mass: 556.717 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H40N4O5S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 237 / 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: 2.61 Å3/Da / Density % sol: 52.93 %
Crystal growTemperature: 293 K / Method: under oil / pH: 7.8
Details: 9.7mg/ml protein, 0.6mM GSK-3 beta peptide, 1mM Mg-AMPPNP, 10mM DTT, 22% PEG 4K, 10% Isopropanol, 0.1M Hepes, pH 7.8, Under oil, temperature 293K

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Feb 8, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. all: 29670 / Num. obs: 29146 / % possible obs: 98.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.34 % / Rmerge(I) obs: 0.15 / Rsym value: 0.12 / Net I/σ(I): 11.1
Reflection shellResolution: 1.9→2 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 2.5 / Num. unique all: 2257 / Rsym value: 0.31 / % possible all: 87.9

-
Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→20.68 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.927 / SU B: 3.614 / SU ML: 0.107 / Cross valid method: THROUGHOUT / ESU R Free: 0.154 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.24299 1479 5.1 %RANDOM
Rwork0.19336 ---
obs0.19594 27656 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 40.551 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20 Å20.37 Å2
2---0.73 Å20 Å2
3---0.82 Å2
Refinement stepCycle: LAST / Resolution: 1.9→20.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2683 0 39 237 2959
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0222790
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.471.9853760
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2085325
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.4423.333135
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.42815497
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9911520
X-RAY DIFFRACTIONr_chiral_restr0.1070.2388
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212121
X-RAY DIFFRACTIONr_gen_planes_other
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_it0.8011.51629
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.50122621
X-RAY DIFFRACTIONr_scbond_it2.26331161
X-RAY DIFFRACTIONr_scangle_it3.7024.51139
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.294 29 -
Rwork0.269 704 -
obs--100 %

+
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://pdbjlvh1.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