| Structural highlights
6bsx is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.65Å |
| Ligands: | ACT, E7S, EDO, GDP, MG |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
RHEB_HUMAN Stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling. Activates the protein kinase activity of mTORC1. Has low intrinsic GTPase activity.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling. NR1 potently inhibits mTORC1 driven phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) but does not inhibit phosphorylation of AKT or ERK. In contrast to rapamycin, NR1 does not cause inhibition of mTORC2 upon prolonged treatment. Furthermore, NR1 potently and selectively inhibits mTORC1 in mouse kidney and muscle in vivo. The data presented herein suggest that pharmacological inhibition of Rheb is an effective approach for selective inhibition of mTORC1 with therapeutic potential.
A small molecule inhibitor of Rheb selectively targets mTORC1 signaling.,Mahoney SJ, Narayan S, Molz L, Berstler LA, Kang SA, Vlasuk GP, Saiah E Nat Commun. 2018 Feb 7;9(1):548. doi: 10.1038/s41467-018-03035-z. PMID:29416044[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13571-6. Epub 2002 Sep 23. PMID:12271141 doi:10.1073/pnas.202476899
- ↑ Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003 Aug 1;17(15):1829-34. Epub 2003 Jul 17. PMID:12869586 doi:10.1101/gad.1110003
- ↑ Li Y, Inoki K, Guan KL. Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Mol Cell Biol. 2004 Sep;24(18):7965-75. PMID:15340059 doi:10.1128/MCB.24.18.7965-7975.2004
- ↑ Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol. 2005 Apr 26;15(8):702-13. PMID:15854902 doi:S0960-9822(05)00226-5
- ↑ Tee AR, Blenis J, Proud CG. Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1. FEBS Lett. 2005 Aug 29;579(21):4763-8. PMID:16098514 doi:10.1016/j.febslet.2005.07.054
- ↑ Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010 Apr 16;141(2):290-303. doi: 10.1016/j.cell.2010.02.024. Epub 2010 Apr , 8. PMID:20381137 doi:10.1016/j.cell.2010.02.024
- ↑ Mahoney SJ, Narayan S, Molz L, Berstler LA, Kang SA, Vlasuk GP, Saiah E. A small molecule inhibitor of Rheb selectively targets mTORC1 signaling. Nat Commun. 2018 Feb 7;9(1):548. doi: 10.1038/s41467-018-03035-z. PMID:29416044 doi:https://dx.doi.org/10.1038/s41467-018-03035-z
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