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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


positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process / 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 / macrolide binding / regulation of membrane permeability ...positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process / 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 / macrolide binding / regulation of membrane permeability / TORC2 complex / cellular response to leucine starvation / TFIIIC-class transcription factor complex binding / heart valve morphogenesis / negative regulation of lysosome organization / voluntary musculoskeletal movement / activin receptor binding / positive regulation of odontoblast differentiation / TORC1 complex / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / calcineurin-NFAT signaling cascade / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / RNA polymerase III type 3 promoter sequence-specific DNA binding / cytoplasmic side of membrane / positive regulation of keratinocyte migration / regulation of osteoclast differentiation / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / MTOR signalling / energy reserve metabolic process / regulation of lysosome organization / cellular response to L-leucine / regulation of autophagosome assembly / Energy dependent regulation of mTOR by LKB1-AMPK / cellular response to nutrient / type I transforming growth factor beta receptor binding / negative regulation of activin receptor signaling pathway / Amino acids regulate mTORC1 / signaling receptor inhibitor activity / heart trabecula formation / cellular response to methionine / negative regulation of cell size / positive regulation of osteoclast differentiation / TORC2 signaling / I-SMAD binding / cellular response to osmotic stress / regulation of amyloid precursor protein catabolic process / terminal cisterna / ryanodine receptor complex / cell projection organization / anoikis / inositol hexakisphosphate binding / cardiac muscle cell development / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of ubiquitin-dependent protein catabolic process / regulation of myelination / negative regulation of protein localization to nucleus / positive regulation of transcription by RNA polymerase III / 'de novo' protein folding / positive regulation of ruffle assembly / regulation of cell size / ventricular cardiac muscle tissue morphogenesis / FK506 binding / positive regulation of myotube differentiation / Macroautophagy / negative regulation of macroautophagy / Constitutive Signaling by AKT1 E17K in Cancer / germ cell development / positive regulation of actin filament polymerization / TGF-beta receptor signaling activates SMADs / oligodendrocyte differentiation / TORC1 signaling / positive regulation of oligodendrocyte differentiation / behavioral response to pain / mTORC1-mediated signalling / TOR signaling / response to amino acid / positive regulation of translational initiation / Calcineurin activates NFAT / CD28 dependent PI3K/Akt signaling / HSF1-dependent transactivation / regulation of macroautophagy / regulation of immune response / positive regulation of TOR signaling / protein serine/threonine kinase inhibitor activity / protein kinase activator activity / enzyme-substrate adaptor activity / 'de novo' pyrimidine nucleobase biosynthetic process / positive regulation of epithelial to mesenchymal transition / social behavior / positive regulation of lipid biosynthetic process / positive regulation of G1/S transition of mitotic cell cycle / vascular endothelial cell response to laminar fluid shear stress / heart morphogenesis / regulation of cellular response to heat / positive regulation of lamellipodium assembly / neuronal action potential / phagocytic vesicle / T cell costimulation / positive regulation of stress fiber assembly
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 / HEAT repeat / HEAT repeat / Rapamycin binding domain / : / Serine/threonine-protein kinase ATR-like, HEAT repeats / Chitinase A; domain 3 - #40 / : / FATC domain / 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. / 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, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / 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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