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• W2998065697 abstract "Abstract Gluconeogenesis, the reverse process of glycolysis, is a favorable mechanism at conditions of glucose deprivation. Pck1 is a rate‐limiting gluconeogenic enzyme, where its deficiency or mutation contributes to serious clinical situations as neonatal hypoglycemia and liver failure. A recent report confirms that Pck1 is a target for proteasomal degradation through its proline residue at the penultimate position, recognized by Gid4 E3 ligase, but with a lack of informative structural details. In this study, we delineate the localized sequence motif, degron, that specifically interact with Gid4 ligase and unravel the binding mode of Pck1 to the Gid4 ligase by using molecular docking and molecular dynamics. The peptide/protein docking HPEPDOCK web server along with molecular dynamic simulations are applied to demonstrate the binding mode and interactions of a Pck1 wild type (SPSK) and mutant (K4V) with the recently solved structure of Gid4 ligase. Results unveil a distinct binding mode of the mutated peptide compared with the wild type despite having comparable binding affinities to Gid4. Moreover, the four‐residue peptide is found insufficient for Gid4 binding, while the seven‐residue peptide suffices for binding to Gid4. The amino acids S134, K135, and N137 in the loop L1 (between β1 and β2) of the Gid4 are essential for the stabilization of the seven‐residue peptide in the binding site of the ligase. The presence of Val 4 instead of Lys 4 smashes the H‐bonds that are formed between Lys 4 and Gid4 in the wild type peptide, making the peptide prone to bind with the other side of the binding pocket (L4 loop of Gid4). The dynamics of Gid4 L3 loop is affected dramatically once K4V mutant Pck1 peptide is introduced. This opens the door to explore the mutation effects on the binding mode and smooth the path to target protein degradation by design competitive and non‐competitive inhibitors." @default.
• W2998065697 created "2020-01-10" @default.
• W2998065697 creator A5027511475 @default.
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• W2998065697 date "2019-12-27" @default.
• W2998065697 modified "2023-09-27" @default.
• W2998065697 title "Recognition of the gluconeogenic enzyme, Pck1, via the Gid4 E3 ligase: An in silico perspective" @default.
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• W2998065697 doi "https://doi.org/10.1002/jmr.2821" @default.
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