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- PDB-8era: RMC-5552 in complex with mTORC1 and FKBP12 -

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Basic information

Entry
Database: PDB / ID: 8era
TitleRMC-5552 in complex with mTORC1 and FKBP12
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP1A
  • Regulatory-associated protein of mTOR
  • Serine/threonine-protein kinase mTOR
  • Target of rapamycin complex subunit LST8
KeywordsCOMPLEX (ISOMERASE/KINASE) / Antitumor / mTORC1 / COMPLEX (ISOMERASE-KINASE) complex
Function / homology
Function and homology information


RNA polymerase III type 2 promoter sequence-specific DNA binding / RNA polymerase III type 1 promoter sequence-specific DNA binding / positive regulation of cytoplasmic translational initiation / regulation of locomotor rhythm / T-helper 1 cell lineage commitment / positive regulation of pentose-phosphate shunt / positive regulation of wound healing, spreading of epidermal cells / TORC2 signaling / TORC2 complex / regulation of membrane permeability ...RNA polymerase III type 2 promoter sequence-specific DNA binding / RNA polymerase III type 1 promoter sequence-specific DNA binding / positive regulation of cytoplasmic translational initiation / regulation of locomotor rhythm / T-helper 1 cell lineage commitment / positive regulation of pentose-phosphate shunt / positive regulation of wound healing, spreading of epidermal cells / TORC2 signaling / TORC2 complex / regulation of membrane permeability / cellular response to leucine starvation / macrolide binding / negative regulation of lysosome organization / heart valve morphogenesis / TFIIIC-class transcription factor complex binding / TORC1 complex / activin receptor binding / voluntary musculoskeletal movement / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / positive regulation of odontoblast differentiation / calcineurin-NFAT signaling cascade / RNA polymerase III type 3 promoter sequence-specific DNA binding / positive regulation of keratinocyte migration / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / regulation of osteoclast differentiation / transforming growth factor beta receptor binding / cytoplasmic side of membrane / regulation of lysosome organization / MTOR signalling / TGFBR1 LBD Mutants in Cancer / cellular response to L-leucine / energy reserve metabolic process / type I transforming growth factor beta receptor binding / regulation of autophagosome assembly / Energy dependent regulation of mTOR by LKB1-AMPK / cellular response to nutrient / Amino acids regulate mTORC1 / TORC1 signaling / negative regulation of activin receptor signaling pathway / serine/threonine protein kinase complex / ruffle organization / cellular response to methionine / heart trabecula formation / positive regulation of osteoclast differentiation / negative regulation of cell size / I-SMAD binding / positive regulation of ubiquitin-dependent protein catabolic process / cellular response to osmotic stress / negative regulation of protein localization to nucleus / anoikis / regulation of amyloid precursor protein catabolic process / inositol hexakisphosphate binding / signaling receptor inhibitor activity / cardiac muscle cell development / terminal cisterna / ryanodine receptor complex / negative regulation of calcineurin-NFAT signaling cascade / regulation of myelination / positive regulation of transcription by RNA polymerase III / 'de novo' protein folding / negative regulation of macroautophagy / ventricular cardiac muscle tissue morphogenesis / Macroautophagy / positive regulation of myotube differentiation / FK506 binding / regulation of cell size / Constitutive Signaling by AKT1 E17K in Cancer / positive regulation of actin filament polymerization / germ cell development / behavioral response to pain / TOR signaling / TGF-beta receptor signaling activates SMADs / oligodendrocyte differentiation / positive regulation of oligodendrocyte differentiation / mTORC1-mediated signalling / positive regulation of translational initiation / regulation of ryanodine-sensitive calcium-release channel activity / Calcineurin activates NFAT / social behavior / CD28 dependent PI3K/Akt signaling / protein serine/threonine kinase inhibitor activity / HSF1-dependent transactivation / regulation of macroautophagy / positive regulation of TOR signaling / protein kinase activator activity / enzyme-substrate adaptor activity / positive regulation of G1/S transition of mitotic cell cycle / regulation of immune response / response to amino acid / 'de novo' pyrimidine nucleobase biosynthetic process / positive regulation of epithelial to mesenchymal transition / vascular endothelial cell response to laminar fluid shear stress / positive regulation of lipid biosynthetic process / heart morphogenesis / cellular response to nutrient levels / neuronal action potential / regulation of cellular response to heat / positive regulation of lamellipodium assembly / cardiac muscle contraction / T cell costimulation
Similarity search - Function
Raptor, N-terminal CASPase-like domain / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / Target of rapamycin complex subunit LST8 / Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR ...Raptor, N-terminal CASPase-like domain / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / Target of rapamycin complex subunit LST8 / Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / Rapamycin binding domain / Serine/threonine-protein kinase ATR-like, HEAT repeats / HEAT repeat / HEAT repeat / : / FATC domain / Chitinase A; domain 3 - #40 / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / : / Chitinase A; domain 3 / Quinoprotein alcohol dehydrogenase-like superfamily / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Peptidyl-prolyl cis-trans isomerase domain superfamily / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / WD domain, G-beta repeat / Armadillo-type fold / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Roll / Protein kinase-like domain superfamily / Alpha Beta
Similarity search - Domain/homology
Chem-XYU / Chem-XZ9 / Serine/threonine-protein kinase mTOR / Peptidyl-prolyl cis-trans isomerase FKBP1A / Regulatory-associated protein of mTOR / Target of rapamycin complex subunit LST8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.86 Å
AuthorsTomlinson, A.C.A. / Yano, J.K.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: J Med Chem / Year: 2023
Title: Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.
Authors: G Leslie Burnett / Yu C Yang / James B Aggen / Jennifer Pitzen / Micah K Gliedt / Chris M Semko / Abby Marquez / James W Evans / Gang Wang / Walter S Won / Aidan C A Tomlinson / Gert Kiss / ...Authors: G Leslie Burnett / Yu C Yang / James B Aggen / Jennifer Pitzen / Micah K Gliedt / Chris M Semko / Abby Marquez / James W Evans / Gang Wang / Walter S Won / Aidan C A Tomlinson / Gert Kiss / Christos Tzitzilonis / Arun P Thottumkara / James Cregg / Kevin T Mellem / Jong S Choi / Julie C Lee / Yongyuan Zhao / Bianca J Lee / Justin G Meyerowitz / John E Knox / Jingjing Jiang / Zhican Wang / David Wildes / Zhengping Wang / Mallika Singh / Jacqueline A M Smith / Adrian L Gill /
Abstract: Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of ...Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS shows increased antitumor activity in a preclinical model of mutant NSCLC that exhibits resistance to KRAS inhibitor monotherapy.
History
DepositionOct 11, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase mTOR
B: Peptidyl-prolyl cis-trans isomerase FKBP1A
C: Target of rapamycin complex subunit LST8
Y: Regulatory-associated protein of mTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)487,6926
Polymers486,2924
Non-polymers1,4012
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 4 types, 4 molecules ABCY

#1: Protein Serine/threonine-protein kinase mTOR / FK506-binding protein 12-rapamycin complex-associated protein 1 / FKBP12-rapamycin complex- ...FK506-binding protein 12-rapamycin complex-associated protein 1 / FKBP12-rapamycin complex-associated protein / Mammalian target of rapamycin / mTOR / Mechanistic target of rapamycin / Rapamycin and FKBP12 target 1 / Rapamycin target protein 1


Mass: 289257.969 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MTOR, FRAP, FRAP1, FRAP2, RAFT1, RAPT1 / Production host: Homo sapiens (human)
References: UniProt: P42345, non-specific serine/threonine protein kinase
#2: Protein Peptidyl-prolyl cis-trans isomerase FKBP1A / PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506-binding ...PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506-binding protein 1A / FKBP-1A / Immunophilin FKBP12 / Rotamase


Mass: 11923.586 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1A, FKBP1, FKBP12 / Production host: Escherichia coli (E. coli) / References: UniProt: P62942, peptidylprolyl isomerase
#3: Protein Target of rapamycin complex subunit LST8 / TORC subunit LST8 / G protein beta subunit-like / Protein GbetaL / Mammalian lethal with SEC13 ...TORC subunit LST8 / G protein beta subunit-like / Protein GbetaL / Mammalian lethal with SEC13 protein 8 / mLST8


Mass: 35910.090 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MLST8, GBL, LST8 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9BVC4
#4: Protein Regulatory-associated protein of mTOR / Raptor / p150 target of rapamycin (TOR)-scaffold protein


Mass: 149200.016 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RPTOR, KIAA1303, RAPTOR / Production host: Homo sapiens (human) / References: UniProt: Q8N122

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-XZ9 / 1-[6-{[(3M)-4-amino-3-(2-amino-1,3-benzoxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]-3-hydroxypropan-1-one


Mass: 484.510 Da / Num. of mol.: 1
Fragment: Entity 5 XZ9 and Entity 6 XYU are connected by an unmodeled PEG linker.
Source method: obtained synthetically / Formula: C25H24N8O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-XYU / (3S,5R,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,30R,34aS)-5,9,27-trihydroxy-3-{(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl}-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontine-1,11,28,29(4H,31H)-tetrone


Mass: 916.188 Da / Num. of mol.: 1
Fragment: Entity 5 XZ9 and Entity 6 XYU are connected by an unmodeled PEG linker.
Source method: obtained synthetically / Formula: C51H81NO13 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 2D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: RMC-5552-mTORC1-FKBP12 / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.86 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 805027 / Symmetry type: POINT
RefinementCross valid method: NONE
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00529490
ELECTRON MICROSCOPYf_angle_d1.176940008
ELECTRON MICROSCOPYf_chiral_restr0.05364505
ELECTRON MICROSCOPYf_plane_restr0.00955110
ELECTRON MICROSCOPYf_dihedral_angle_d6.63623953

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