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Università degli Studi di Milano Facoltà di Farmacia

Università degli Studi di Milano Facoltà di Farmacia. Modelling the folding of transmembrane proteins using a novel fragmental approach: the human ghrelin receptor and the glutamate transporter EAAT1. Alessandro Pedretti & Giulio Vistoli. The fragmental approach 1. Aminoacid sequence

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Università degli Studi di Milano Facoltà di Farmacia

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  1. Università degli Studi di Milano Facoltà di Farmacia Modelling the folding of transmembrane proteins using a novel fragmental approach: the human ghrelin receptor and the glutamate transporter EAAT1 Alessandro Pedretti & Giulio Vistoli

  2. The fragmental approach1 Aminoacid sequence of the transmembrane protein Fragmentation in structural domains Folding prediction of each fragment Assembling using a global template

  3. Global template

  4. Side chains building Rough model MM/MD refinement Final model Molecular docking Lignads Ligand-protein complexes The fragmental approach2 Model validation

  5. HGHS-R1a ligand binding sites Glu 124 Polar Arg 283 Apolar Spiroindane derivative EC50 = 0.6 nM TM3 TM6

  6. pEC50 pEC50 experimental Scorepol (Kcal/mol) pEC50 calculated pEC50 = 5.96 (0.29) – 0.068 (0.0087) Scorepol – 0.014 (0.0033) Scoreapol n = 35; r2 = 0.72; q2 = 0.67; s = 0.24; F = 42.06 pEC50 = 6.06 (0.35) – 0.070 (0.01) x Scorepol n = 35; r2 = 0.57; q2 = 0.51 s = 0.29; F = 44.30 QSAR analysis

  7. Conclusions • The fragmental approach allows to obtain good models avoiding the construction of bovine rhodopsin clones. • The computational results are confirmed by the good correlation between the experimental data and the docking scores. • The method was successfully applied to the non-GPCR protein EAAT1, obtaining results confirmed by the experimental data.

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