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- PDB-8r3x: Crystal structure of aPKC Iota kinase domain with LLGL2 peptide -

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Basic information

Entry
Database: PDB / ID: 8r3x
TitleCrystal structure of aPKC Iota kinase domain with LLGL2 peptide
Components
  • LLGL scribble cell polarity complex component 2
  • Protein kinase C iota type
KeywordsCYTOSOLIC PROTEIN / Kinase / Polarity / Kinase substrate complex.
Function / homology
Function and homology information


establishment of spindle orientation / regulation of establishment or maintenance of cell polarity / Golgi vesicle budding / PAR polarity complex / Tight junction interactions / diacylglycerol-dependent, calcium-independent serine/threonine kinase activity / calcium,diacylglycerol-dependent serine/threonine kinase activity / protein kinase C / diacylglycerol-dependent serine/threonine kinase activity / establishment of apical/basal cell polarity ...establishment of spindle orientation / regulation of establishment or maintenance of cell polarity / Golgi vesicle budding / PAR polarity complex / Tight junction interactions / diacylglycerol-dependent, calcium-independent serine/threonine kinase activity / calcium,diacylglycerol-dependent serine/threonine kinase activity / protein kinase C / diacylglycerol-dependent serine/threonine kinase activity / establishment of apical/basal cell polarity / L-leucine transport / negative regulation of glial cell apoptotic process / regulation of Notch signaling pathway / eye photoreceptor cell development / myosin II binding / Schmidt-Lanterman incisure / Golgi to plasma membrane transport / establishment or maintenance of epithelial cell apical/basal polarity / cellular response to chemical stress / membrane organization / cell-cell junction organization / tight junction / protein targeting to membrane / cortical actin cytoskeleton organization / cortical actin cytoskeleton / positive regulation of Notch signaling pathway / establishment of cell polarity / cell leading edge / exocytosis / brush border / positive regulation of endothelial cell apoptotic process / bicellular tight junction / regulation of postsynaptic membrane neurotransmitter receptor levels / intercellular bridge / vesicle-mediated transport / positive regulation of glial cell proliferation / cytoskeleton organization / response to interleukin-1 / p75NTR recruits signalling complexes / secretion / GTPase activator activity / actin filament organization / protein localization to plasma membrane / PDZ domain binding / positive regulation of D-glucose import / adherens junction / positive regulation of protein localization to plasma membrane / Schaffer collateral - CA1 synapse / positive regulation of neuron projection development / phospholipid binding / Pre-NOTCH Transcription and Translation / cellular response to insulin stimulus / positive regulation of NF-kappaB transcription factor activity / KEAP1-NFE2L2 pathway / cell migration / microtubule cytoskeleton / negative regulation of neuron apoptotic process / protein kinase activity / endosome / intracellular signal transduction / cilium / protein phosphorylation / apical plasma membrane / Golgi membrane / cell division / protein serine kinase activity / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / negative regulation of apoptotic process / glutamatergic synapse / extracellular exosome / zinc ion binding / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Lethal(2) giant larvae protein / Lethal giant larvae homologue 2 / LLGL2 / Atypical protein kinase C iota type, catalytic domain / Protein kinase C / Protein kinase C, PB1 domain / PB1 domain / PB1 domain / PB1 domain / : ...Lethal(2) giant larvae protein / Lethal giant larvae homologue 2 / LLGL2 / Atypical protein kinase C iota type, catalytic domain / Protein kinase C / Protein kinase C, PB1 domain / PB1 domain / PB1 domain / PB1 domain / : / PB1 domain profile. / Protein kinase, C-terminal / Protein kinase C terminal domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / WD40 repeats / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40 repeat / WD40-repeat-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Protein kinase C iota type / LLGL scribble cell polarity complex component 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.591 Å
AuthorsSoriano, E.V. / Earl, C.P. / Briggs, D.C. / McDonald, N.Q.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Wellcome TrustCC2068 United Kingdom
Cancer Research UKCC2026 United Kingdom
Medical Research Council (MRC, United Kingdom)CC2068 United Kingdom
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Capture, mutual inhibition and release mechanism for aPKC-Par6 and its multisite polarity substrate Lgl.
Authors: Christopher P Earl / Mathias Cobbaut / André Barros-Carvalho / Marina E Ivanova / David C Briggs / Eurico Morais-de-Sá / Peter J Parker / Neil Q McDonald /
Abstract: The mutually antagonistic relationship of atypical protein kinase C (aPKC) and partitioning-defective protein 6 (Par6) with the substrate lethal (2) giant larvae (Lgl) is essential for regulating ...The mutually antagonistic relationship of atypical protein kinase C (aPKC) and partitioning-defective protein 6 (Par6) with the substrate lethal (2) giant larvae (Lgl) is essential for regulating polarity across many cell types. Although aPKC-Par6 phosphorylates Lgl at three serine sites to exclude it from the apical domain, aPKC-Par6 and Lgl paradoxically form a stable kinase-substrate complex, with conflicting roles proposed for Par6. We report the structure of human aPKCι-Par6α bound to full-length Llgl1, captured through an aPKCι docking site and a Par6 contact. This complex traps a phospho-S663 Llgl1 intermediate bridging between aPKC and Par6, impeding phosphorylation progression. Thus, aPKCι is effectively inhibited by Llgl1 while Llgl1 is captured by aPKCι-Par6. Mutational disruption of the Lgl-aPKC interaction impedes complex assembly and Lgl phosphorylation, whereas disrupting the Lgl-Par6 contact promotes complex dissociation and Lgl phosphorylation. We demonstrate a Par6-regulated substrate capture-and-release model requiring binding by active Cdc42 and the apical partner Crumbs to drive complex disassembly. Our results suggest a mechanism for mutual regulation and spatial control of aPKC-Par6 and Lgl activities.
History
DepositionNov 10, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 20, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Apr 23, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein kinase C iota type
B: Protein kinase C iota type
C: LLGL scribble cell polarity complex component 2
D: LLGL scribble cell polarity complex component 2


Theoretical massNumber of molelcules
Total (without water)86,9384
Polymers86,9384
Non-polymers00
Water724
1
A: Protein kinase C iota type
C: LLGL scribble cell polarity complex component 2


Theoretical massNumber of molelcules
Total (without water)43,4692
Polymers43,4692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1680 Å2
ΔGint-3 kcal/mol
Surface area16510 Å2
MethodPISA
2
B: Protein kinase C iota type
D: LLGL scribble cell polarity complex component 2


Theoretical massNumber of molelcules
Total (without water)43,4692
Polymers43,4692
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1620 Å2
ΔGint-2 kcal/mol
Surface area16610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.418, 86.324, 114.803
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Protein kinase C iota type / Atypical protein kinase C-lambda/iota / PRKC-lambda/iota / aPKC-lambda/iota / nPKC-iota


Mass: 40981.039 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKCI, DXS1179E / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41743, protein kinase C
#2: Protein/peptide LLGL scribble cell polarity complex component 2 / HGL / Lethal(2) giant larvae protein homolog 2


Mass: 2488.037 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q6P1M3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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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: 2.23 Å3/Da / Density % sol: 44.77 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: Morpheus Condition: 25% (v/v) MPD, 25% (v/v) PEG 1000, 25% (v/v) PEG 3350, 0.3 M NaNO3, 0.3 M Na2HPO4, 0.3 M (NH4)2SO4, 0.1 M MES/imidazole pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9787 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 7, 2011 / Details: ACCEL Fixed exit Double Crystal
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 2.59→114.8 Å / Num. obs: 24903 / % possible obs: 100 % / Redundancy: 6.5 % / Biso Wilson estimate: 55.91 Å2 / CC1/2: 0.995 / Net I/σ(I): 8.6
Reflection shellResolution: 2.59→2.64 Å / Mean I/σ(I) obs: 0.5 / Num. unique obs: 1203 / CC1/2: 0.269

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
xia23.8.6data reduction
DIALS3.8data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.591→68.995 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.912 / WRfactor Rfree: 0.223 / WRfactor Rwork: 0.183 / Average fsc free: 0.9286 / Average fsc work: 0.9386 / Cross valid method: FREE R-VALUE / ESU R: 1.802 / ESU R Free: 0.35
Details: Hydrogens have been used if present in the input file
RfactorNum. reflection% reflection
Rfree0.2692 1234 4.98 %
Rwork0.2319 23544 -
all0.234 --
obs-24778 99.618 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 65.637 Å2
Baniso -1Baniso -2Baniso -3
1-0.217 Å2-0 Å2-0 Å2
2---2.671 Å20 Å2
3---2.454 Å2
Refinement stepCycle: LAST / Resolution: 2.591→68.995 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5710 0 0 4 5714
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0125851
X-RAY DIFFRACTIONr_angle_refined_deg1.5571.8387904
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9355698
X-RAY DIFFRACTIONr_dihedral_angle_2_deg9.442542
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.586101030
X-RAY DIFFRACTIONr_dihedral_angle_6_deg13.88210308
X-RAY DIFFRACTIONr_chiral_restr0.0810.2836
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024510
X-RAY DIFFRACTIONr_nbd_refined0.1830.22159
X-RAY DIFFRACTIONr_nbtor_refined0.290.23936
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1230.2155
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1930.246
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1290.28
X-RAY DIFFRACTIONr_mcbond_it2.9916.3992798
X-RAY DIFFRACTIONr_mcangle_it4.95611.5513491
X-RAY DIFFRACTIONr_scbond_it2.9986.6613053
X-RAY DIFFRACTIONr_scangle_it5.19312.1664412
X-RAY DIFFRACTIONr_lrange_it8.01769.9178122
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.591-2.6580.3731110.37816750.37818200.8740.86798.13190.394
2.658-2.7310.419610.38316820.38417580.8410.87599.14680.397
2.731-2.810.374690.35516360.35517120.9050.89699.59110.365
2.81-2.8960.356750.33415690.33516550.8990.90399.33540.34
2.896-2.9910.309730.32515500.32516310.9260.92399.50950.322
2.991-3.0960.369860.31514710.31815620.9150.92599.67990.305
3.096-3.2130.38620.27714480.2815140.9030.94299.73580.264
3.213-3.3440.319820.26713740.2714580.9350.94899.86280.237
3.344-3.4920.307730.25913210.26213960.9330.95599.85670.23
3.492-3.6620.274710.24212690.24413410.9460.96399.92540.213
3.662-3.8590.239660.2212090.22112760.9560.9799.92160.192
3.859-4.0930.25550.20811890.2112440.9520.9721000.181
4.093-4.3740.25580.18210770.18511350.9630.981000.157
4.374-4.7230.263540.17310140.17610690.9650.98299.90650.146
4.723-5.1710.212760.1639140.1679910.9650.98499.89910.133
5.171-5.7780.259400.1988780.29200.9720.97699.78260.162
5.778-6.6640.252390.2167630.2188030.9510.97499.87550.182
6.664-8.1420.187310.1666580.1676890.9820.9841000.136
8.142-11.4350.143270.1525290.1525560.9890.9861000.139
11.435-68.9950.304250.2543170.2573420.9460.9581000.238

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