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- PDB-9o5e: The dimeric KICSTOR-GATOR1 supercomplex -

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Basic information

Entry
Database: PDB / ID: 9o5e
TitleThe dimeric KICSTOR-GATOR1 supercomplex
Components
  • GATOR complex protein NPRL2
  • GATOR complex protein NPRL3
  • GATOR1 complex protein DEPDC5
  • KICSTOR complex protein SZT2
KeywordsCELL CYCLE / Lysosome / GATOR1 / KICSTOR / cell growth / amino acid sensing / mTOR / KPTN / ITFG2 / C12orf66 / SZT2 / NPRL2 / NPRL3 / DEPDC5
Function / homology
Function and homology information


regulation of superoxide dismutase activity / KICSTOR complex / GATOR1 complex / negative regulation of kinase activity / corpus callosum morphogenesis / aorta morphogenesis / protein localization to lysosome / Amino acids regulate mTORC1 / cardiac muscle tissue development / vacuolar membrane ...regulation of superoxide dismutase activity / KICSTOR complex / GATOR1 complex / negative regulation of kinase activity / corpus callosum morphogenesis / aorta morphogenesis / protein localization to lysosome / Amino acids regulate mTORC1 / cardiac muscle tissue development / vacuolar membrane / ventricular septum development / pigmentation / roof of mouth development / cellular response to glucose starvation / negative regulation of TORC1 signaling / positive regulation of autophagy / GTPase activator activity / cellular response to amino acid starvation / central nervous system development / post-embryonic development / small GTPase binding / peroxisome / lysosome / intracellular signal transduction / lysosomal membrane / protein-containing complex binding / perinuclear region of cytoplasm / cytosol
Similarity search - Function
Protein SZT2 / : / IML1 N-terminal double psi beta barrel domain / Nitrogen permease regulator 3 / Nitrogen permease regulator 2 / Vacuolar membrane-associated protein Iml1 / DEPDC5 protein, C-terminal / : / : / Nitrogen Permease regulator of amino acid transport activity 3 ...Protein SZT2 / : / IML1 N-terminal double psi beta barrel domain / Nitrogen permease regulator 3 / Nitrogen permease regulator 2 / Vacuolar membrane-associated protein Iml1 / DEPDC5 protein, C-terminal / : / : / Nitrogen Permease regulator of amino acid transport activity 3 / Nitrogen permease regulator 2 / Vacuolar membrane-associated protein Iml1, N-terminal domain / DEPDC5 protein C-terminal region / GATOR1 complex protein NPRL3, C-terminal HTH / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
GATOR1 complex protein DEPDC5 / GATOR1 complex protein NPRL3 / KICSTOR complex protein SZT2 / GATOR1 complex protein NPRL2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5 Å
AuthorsBayly-Jones, C. / Lupton, C.J. / Chang, Y.G. / Ellisdon, A.M.
Funding support Australia, 4items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP2036864 Australia
Australian Research Council (ARC)DE240100992 Australia
Other governmentMCRF21036 Australia
Australian Research Council (ARC)LE170100016 Australia
CitationJournal: Cell / Year: 2026
Title: Structure of the lysosomal KICSTOR-GATOR1-SAMTOR nutrient-sensing supercomplex.
Authors: Christopher J Lupton / Charles Bayly-Jones / Shuqi Dong / Terrance Lam / Wentong Luo / Gareth D Jones / Chantel Mastos / Nicholas J Frescher / San S Lim / Alastair C Keen / Luke E Formosa / ...Authors: Christopher J Lupton / Charles Bayly-Jones / Shuqi Dong / Terrance Lam / Wentong Luo / Gareth D Jones / Chantel Mastos / Nicholas J Frescher / San S Lim / Alastair C Keen / Luke E Formosa / Hari Venugopal / Yong-Gang Chang / Michelle L Halls / Andrew M Ellisdon /
Abstract: The guanosine triphosphate (GTP)-bound state of the heterodimeric Rag GTPases functions as a molecular switch regulating mechanistic target of rapamycin complex 1 (mTORC1) activation at the lysosome ...The guanosine triphosphate (GTP)-bound state of the heterodimeric Rag GTPases functions as a molecular switch regulating mechanistic target of rapamycin complex 1 (mTORC1) activation at the lysosome downstream of amino acid fluctuations. Under low amino acid conditions, GTPase-activating protein (GAP) activity toward Rags 1 (GATOR1) promotes RagA GTP hydrolysis, preventing mTORC1 activation. KICSTOR recruits and regulates GATOR1 at the lysosome by undefined mechanisms. Here, we resolve the KICSTOR-GATOR1 structure, revealing a striking ∼60-nm crescent-shaped assembly. GATOR1 anchors to KICSTOR via an extensive interface, and mutations that disrupt this interaction impair mTORC1 regulation. The S-adenosylmethionine sensor SAMTOR binds KICSTOR in a manner incompatible with metabolite binding, providing structural insight into methionine sensing via SAMTOR-KICSTOR association. We discover that KICSTOR and GATOR1 form a dimeric supercomplex. This assembly restricts GATOR1 to an orientation that favors the low-affinity active GAP mode of Rag GTPase engagement while sterically restricting access to the high-affinity inhibitory mode, consistent with a model of an active lysosomal GATOR1 docking complex.
History
DepositionApr 10, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 21, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: GATOR complex protein NPRL3
D: GATOR complex protein NPRL2
E: KICSTOR complex protein SZT2
H: GATOR1 complex protein DEPDC5
F: GATOR complex protein NPRL3
G: GATOR complex protein NPRL2
I: KICSTOR complex protein SZT2
J: GATOR1 complex protein DEPDC5


Theoretical massNumber of molelcules
Total (without water)1,350,3268
Polymers1,350,3268
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein GATOR complex protein NPRL3 / -14 gene protein / Alpha-globin regulatory element-containing gene protein / Nitrogen permease ...-14 gene protein / Alpha-globin regulatory element-containing gene protein / Nitrogen permease regulator 3-like protein / Protein CGTHBA


Mass: 65769.000 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPRL3, C16orf35, CGTHBA, MARE / Production host: Homo sapiens (human) / References: UniProt: Q12980
#2: Protein GATOR complex protein NPRL2 / Gene 21 protein / G21 protein / Nitrogen permease regulator 2-like protein / NPR2-like protein / ...Gene 21 protein / G21 protein / Nitrogen permease regulator 2-like protein / NPR2-like protein / Tumor suppressor candidate 4


Mass: 45799.547 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPRL2, TUSC4 / Production host: Homo sapiens (human) / References: UniProt: Q8WTW4
#3: Protein KICSTOR complex protein SZT2 / Seizure threshold 2 protein homolog


Mass: 380386.500 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SZT2, C1orf84, KIAA0467 / Production host: Homo sapiens (human) / References: UniProt: Q5T011
#4: Protein GATOR1 complex protein DEPDC5 / DEP domain-containing protein 5


Mass: 183207.703 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DEPDC5, KIAA0645 / Production host: Homo sapiens (human) / References: UniProt: O75140
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Dimeric supercomplex of KICSTOR-GATOR1COMPLEXall0RECOMBINANT
2dimeric GATOR1 subcomplexCOMPLEX#1-#2, #41RECOMBINANT
3SZT2 component of the KICSTOR subcomplexCOMPLEX#31RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
11NO
210.582 MDaYES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenConc.: 0.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 278 K

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Electron microscopy imaging

MicroscopyModel: TFS TALOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 1 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 5 Å / Resolution method: OTHER / Num. of particles: 13688 / Details: Average nominal resolution of composite / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT
RefinementHighest resolution: 5 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00343220
ELECTRON MICROSCOPYf_angle_d0.60658698
ELECTRON MICROSCOPYf_dihedral_angle_d12.29515942
ELECTRON MICROSCOPYf_chiral_restr0.0416632
ELECTRON MICROSCOPYf_plane_restr0.0047472

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