6bt0
CRYSTAL STRUCTURE OF RHEB IN COMPLEX WITH COMPOUND NR1
Structural highlights
FunctionRHEB_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 PubMedThe 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 AlsoReferences
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