000			03250cam a2200337 a 4500
003			EG-GiCUC
005			20250223032543.0
008			200819s2020 ua h f m 000 0 eng d
040			_aEG-GiCUC _beng _cEG-GiCUC
041	0		_aeng
049			_aDeposite
097			_aPh.D
099			_aCai01.12.04.Ph.D.2020.Al.A
100	0		_aAlaa Mamdouh Abdallah Ismail Elgohary
245	1	0	_aAltered recognition by the protein degradation machinery re-programmes proteostasis in cancer cells / _cAlaa Mamdouh Abdallah Ismail Elgohary ; Supervised Wael M. Elshemey , Richard P. Fahlman
246	1	5	_a التعرف المتغير بواسطة آلية تكسير البروتين تعيد برمجة ثبات البروتين في الخلايا السرطانية
260			_aCairo : _bAlaa Mamdouh Abdallah Ismail Elgohary , _c2020
300			_a99 P. : _bfacsmailies ; _c25cm
502			_aThesis (Ph.D.) - Cairo University - Faculty of Science - Department of Biophysics
520			_aGluconeogenesis, 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 Ý1 and Ý2) of the Gid4 are essential for the stabilization of the seven-residue peptide in the binding site of the ligase. The presence of Val4 instead of Lys4 smashes the Hbonds that are formed between Lys4 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
530			_aIssued also as CD
653		4	_aDocking
653		4	_aGid4 E3 ligase
653		4	_aGluconeogenesis
700	0		_aRichard P. Fahlman , _eSupervisor
700	0		_aWael M. Elshemey, _eSupervisor
856			_uhttp://172.23.153.220/th.pdf
905			_aAmira _eCataloger
905			_aNazla _eRevisor
942			_2ddc _cTH
999			_c77291 _d77291