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The autophagy-related Atg proteins Atg5, Atg12 and Atg16 also have a role in this process, by promoting the formation of the autophagosome precursor, the phagophore. Cells can use the products of autophagic degradation to generate energy or other essential proteins required for cell survival. Autophagy is a conserved catabolic cellular process in which macromolecules and organelles are degraded, either as a means to eliminate long-lived, damaged, or faulty cellular components, or in response to stresses such as hypoxia, endoplasmic reticulum stress, or nutrient deprivation. Abstract Opioid analgesics are the most efficient tool in pain management; however, high tolerance and addiction liabilities also make them the most abused class of medication, resulting in millions of cases of drug overdose and more than 15, deaths in the US each year. Two widely used drugs are known to inhibit autophagy: The structures reveal atomic details of ligand binding and provide a reliable 3D framework for rational discovery of new ligands targeting orthosteric or allosteric pockets of DOR.

Newdor


The project will primarily focus on two therapeutically beneficial profiles: When cellular conditions are favourable, autophagy is negatively regulated by the nutrient sensor mammalian target of rapamycin mTOR. Both initial screening and lead optimization phases will employ state-of-the-art structure-based approaches which have proven to be highly effective in recent applications to GPCRs. The autophagy-related Atg proteins Atg5, Atg12 and Atg16 also have a role in this process, by promoting the formation of the autophagosome precursor, the phagophore. Two studies in this issue of EMBO reports provide new insight into the autophagic process. The structures reveal atomic details of ligand binding and provide a reliable 3D framework for rational discovery of new ligands targeting orthosteric or allosteric pockets of DOR. Specific modulation of d-opioid receptor DOR represents one of the most promising strategies to control tolerance and addiction to opioid drugs; however, only a few chemotypes of DOR-selective compounds have been explored. Autophagy is a conserved catabolic cellular process in which macromolecules and organelles are degraded, either as a means to eliminate long-lived, damaged, or faulty cellular components, or in response to stresses such as hypoxia, endoplasmic reticulum stress, or nutrient deprivation. This project will target one of the less developed opioid subtypes, d-opioid receptor, known to mediate long-term pain relief without inducing 'highs' or generating tolerance. The most promising chemical scaffolds, and validated structural models will be employed then in an iterative lead optimization at the R33 phase. Cells can use the products of autophagic degradation to generate energy or other essential proteins required for cell survival. Through a poorly defined process, this complex initiates the nucleation of the autophagosome membrane. Two widely used drugs are known to inhibit autophagy: In the presence of stress, mTOR is inhibited and autophagy is induced Fig 1. Public Health Relevance A growing epidemic of painkiller abuse makes development of a new generation of medications with reduced risks of tolerance, addiction, and overdosing, a holy grail for pain management therapies. In the exploratory R21 phase of the project we will perform large scale structure-based virtual ligand screening of more than 6 million available compounds to select small sets of candidate hits, and then experimentally test and identify new bifunctional and allosteric ligands. Abstract Opioid analgesics are the most efficient tool in pain management; however, high tolerance and addiction liabilities also make them the most abused class of medication, resulting in millions of cases of drug overdose and more than 15, deaths in the US each year. The project will take advantage of recently developed detailed knowledge of this receptor atomistic structure, advanced molecular design capabilities and experimental testing to discover new synthetic molecules that can be developed into new generation of addiction free pain therapies. The proteins LC3 and GATE16 localize to the autophagosomal membrane during autophagosome formation and remain bound as it fuses with a lysosome and becomes an autolysosome, the end organelle where autophagic substrates are degraded. Mauvezin and colleagues show that a nuclear protein, known as DOR, is a new player in stress-induced autophagy, and the Dikic lab reports that the mitochondrial protein Nix is a selective autophagy receptor that mediates mitochondrial clearance Novak et al, Success of the program will result in new insights into drug action, lead to new DOR ligands with desired properties, and establish a solid platform for rational structure-based discovery of safer and less addictive opioid therapies. Despite a significant body of literature identifying the main regulators of autophagy in model organisms, there are gaps in our understanding of the precise molecular and biochemical modulators that control this adaptive process in metazoans.

Newdor

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Vudobar

26.04.2018 at 10:12 pm
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Despite a significant body of literature identifying the main regulators of autophagy in model organisms, there are gaps in our understanding of the precise molecular and biochemical modulators that control this adaptive process in metazoans.

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