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Open data
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Basic information
Entry | Database: PDB / ID: 8er7 | ||||||
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Title | FKBP12-FRB in Complex with Compound 12 | ||||||
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![]() | COMPLEX (ISOMERASE/KINASE) / Antitumor / mTORC1 / COMPLEX (ISOMERASE-KINASE) complex | ||||||
Function / homology | ![]() regulation of nucleobase-containing compound metabolic process / positive regulation of response to stimulus / response to chemical / response to stress / regulation of cellular response to stress / macrolide binding / activin receptor binding / TORC1 complex / cytoplasmic side of membrane / signaling receptor inhibitor activity ...regulation of nucleobase-containing compound metabolic process / positive regulation of response to stimulus / response to chemical / response to stress / regulation of cellular response to stress / macrolide binding / activin receptor binding / TORC1 complex / cytoplasmic side of membrane / signaling receptor inhibitor activity / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / type I transforming growth factor beta receptor binding / negative regulation of activin receptor signaling pathway / heart trabecula formation / terminal cisterna / ryanodine receptor complex / I-SMAD binding / regulation of amyloid precursor protein catabolic process / protein maturation by protein folding / ventricular cardiac muscle tissue morphogenesis / 'de novo' protein folding / negative regulation of phosphoprotein phosphatase activity / FK506 binding / mTORC1-mediated signalling / TGF-beta receptor signaling activates SMADs / Calcineurin activates NFAT / regulation of immune response / protein peptidyl-prolyl isomerization / supramolecular fiber organization / heart morphogenesis / regulation of ryanodine-sensitive calcium-release channel activity / sarcoplasmic reticulum membrane / positive regulation of protein metabolic process / T cell activation / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / peptidylprolyl isomerase / sarcoplasmic reticulum / peptidyl-prolyl cis-trans isomerase activity / calcium ion transmembrane transport / negative regulation of transforming growth factor beta receptor signaling pathway / Z disc / SARS-CoV-1 activates/modulates innate immune responses / regulation of protein localization / protein folding / positive regulation of protein binding / protein refolding / peptidyl-serine phosphorylation / positive regulation of canonical NF-kappaB signal transduction / transmembrane transporter binding / amyloid fibril formation / Potential therapeutics for SARS / non-specific serine/threonine protein kinase / protein serine/threonine kinase activity / protein-containing complex binding / ATP binding / membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Tomlinson, A.C.A. / Yano, J.K. | ||||||
Funding support | ![]()
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![]() | ![]() 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. #1: ![]() Title: Towards automated crystallographic structure refinement with phenix.refine. Authors: Afonine, P.V. / Grosse-Kunstleve, R.W. / Echols, N. / Headd, J.J. / Moriarty, N.W. / Mustyakimov, M. / Terwilliger, T.C. / Urzhumtsev, A. / Zwart, P.H. / Adams, P.D. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 298.8 KB | Display | ![]() |
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PDB format | ![]() | 219.5 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.7 MB | Display | ![]() |
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Full document | ![]() | 1.7 MB | Display | |
Data in XML | ![]() | 24.9 KB | Display | |
Data in CIF | ![]() | 32.3 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8er6C ![]() 8eraC ![]() 1fapS S: Starting model for refinement C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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1 | ![]()
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2 | ![]()
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3 | ![]()
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Unit cell |
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Components
#1: Protein | Mass: 11923.586 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #2: Protein | Mass: 11388.987 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: B1AKP8, non-specific serine/threonine protein kinase #3: Chemical | #4: Chemical | #5: Water | ChemComp-HOH / | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 4.09 Å3/Da / Density % sol: 69.94 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, hanging drop Details: 3.0-3.3 M sodium formate and 0.1 M HEPES pH 7.0-7.5 PH range: 7.0-7.5 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Oct 23, 2017 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.99993 Å / Relative weight: 1 |
Reflection | Resolution: 3.07→45.91 Å / Num. obs: 21756 / % possible obs: 95.8 % / Redundancy: 4.2 % / Biso Wilson estimate: 92.86 Å2 / Rrim(I) all: 0.082 / Rsym value: 0.072 / Net I/σ(I): 11.06 |
Reflection shell | Resolution: 3.07→3.32 Å / Mean I/σ(I) obs: 2.88 / Num. unique obs: 2054 / Rrim(I) all: 0.0486 / Rsym value: 0.0427 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 1FAP Resolution: 3.07→45.91 Å / SU ML: 0.3504 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 32.8029 Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 119.85 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 3.07→45.91 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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