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3. Why are terephthalamide (right) based compounds able to disrupt Bak/Bcl-XL (left) protein-protein interaction? (3 points).

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  1. B-cell lymphoma-extra large (Bcl-xL) protein is involved in the anti- and pro-apoptotic activity as its tBH1, BH2 and BH3 domains form a hydrophobic cleft, which is the site for interactions with the pro-death proteins, Bax and Bak.
  2. The NMR solution structure of Bcl-xL bound to a Bak BH3 domain peptide shows the Bak peptide forms an amphipathic α-helix, which binds via the hydrophobic side chains of the Val74, Leu78, Ile81 and Ile85 residues ( as evident from pic) into a hydrophobic groove on the surface of Bcl-xL
  3. Terephthalamide mimics α-Helix side chain interactions of the Bak peptide as Bcl-xL inhibitors as it inhibits the BH3 domain of Bak binding to Bcl-xL
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