{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T19:55:10Z","timestamp":1771012510022,"version":"3.50.1"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,12,27]],"date-time":"2019-12-27T00:00:00Z","timestamp":1577404800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Molecular Recognition"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Gluconeogenesis, the reverse process of glycolysis, is a favorable mechanism at conditions of glucose deprivation. Pck1 is a rate\u2010limiting 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\u2010residue peptide is found insufficient for Gid4 binding, while the seven\u2010residue peptide suffices for binding to Gid4. The amino acids S134, K135, and N137 in the loop L1 (between \u03b21 and \u03b22) of the Gid4 are essential for the stabilization of the seven\u2010residue peptide in the binding site of the ligase. The presence of Val<jats:sup>4<\/jats:sup> instead of Lys<jats:sup>4<\/jats:sup> smashes the H\u2010bonds that are formed between Lys<jats:sup>4<\/jats:sup> 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\u2010competitive inhibitors.<\/jats:p>","DOI":"10.1002\/jmr.2821","type":"journal-article","created":{"date-parts":[[2019,12,28]],"date-time":"2019-12-28T03:33:48Z","timestamp":1577504028000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Recognition of the gluconeogenic enzyme, Pck1, via the Gid4 E3 ligase: An in silico perspective"],"prefix":"10.1002","volume":"33","author":[{"given":"Alaa M.","family":"Ismail","sequence":"first","affiliation":[{"name":"Biophysics Department, Faculty of Sciences Cairo University  Giza Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4600-6240","authenticated-orcid":false,"given":"Abdo A.","family":"Elfiky","sequence":"additional","affiliation":[{"name":"Biophysics Department, Faculty of Sciences Cairo University  Giza Egypt"},{"name":"College of Applied Medical Sciences University of Al\u2010Jouf  KSA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wael M.","family":"Elshemey","sequence":"additional","affiliation":[{"name":"Biophysics Department, Faculty of Sciences Cairo University  Giza Egypt"},{"name":"Department of Physics, Faculty of Science Islamic University in Madinah  Medina KSA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,12,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(72)90028-5"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.52.070183.003153"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.4161\/cib.27216"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M113.035600"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2017.02.003"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2016.03.001"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1159\/000489811"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.09.025"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-051710-093308"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.666"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1816596116"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-018-0097-y"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-018-0045-0"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal3655"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-018-0036-1"},{"key":"e_1_2_8_17_1","volume-title":"Molecular Modelling: Principles and Applications","author":"Leach A","year":"2001"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.24934"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.2217\/fvl-2017-0027"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.2217\/fvl-2017-0081"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.24678"},{"key":"e_1_2_8_22_1","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1016\/j.saa.2014.10.045","article-title":"The QSAR and docking calculations of fullerene derivatives as HIV\u20101 protease inhibitors","volume":"136","author":"Saleh NA","year":"2014","journal-title":"Spectrochim Acta A Mol Biomol Spectrosc"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","unstructured":"EzatAA ElfikyAA ElshemeyWM SalehNA.Novel inhibitors against wild\u2010type and mutated HCV NS3 serine protease: an in silico study. 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