5ci7
Structure of ULK1 bound to a selective inhibitor
Structural highlights
FunctionULK1_HUMAN Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK and also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 and PRKAG1, leading to negatively regulate AMPK activity. May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences. Plays a role early in neuronal differentiation and is required for granule cell axon formation.[1] [2] [3] Publication Abstract from PubMedEnergy homeostasis in eukaryotic cells is a complex and fundamental process that is misregulated in several human diseases. A key component of energy regulation is a process called autophagy that involves the recycling of cellular components. There has been much recent interest in studying the mechanism of autophagy to understand an important cellular process and to evaluate the therapeutic potential in targeting autophagy. Activation of a kinase called ULK1 initiates autophagy by driving downstream pathways that lead to the formation of double membrane bound vesicles that surround the cellular contents that are to be degraded. Here, we report the discovery of an inhibitor of ULK1 with improved selectivity and a high-resolution crystal structure of the compound bound to the kinase, which will be useful tools for studying autophagy in cells. Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1.,Lazarus MB, Shokat KM Bioorg Med Chem. 2015 Jul 26. pii: S0968-0896(15)00618-5. doi:, 10.1016/j.bmc.2015.07.034. PMID:26275681[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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