Fig. 1: Identification of an allosteric site adjacent to the activation loop in h-cGASCD and design of an allosteric inhibitor (XL-3156).
From: De novo design of protein condensation inhibitors by targeting an allosteric site of cGAS
a Left, an overall crystal structure of h-cGASCD in complex with RU.521; Right, an enlarged view of interactions between residues and two enantiomers of RU.521 (light blue (S)-RU.521 binds to the orthosteric site and light green (R)-RU.521 engages the allosteric site). b Superimposed structures of DNA-bound cGAS dimer to show three DNA-binding sites: A (green), B (red), and C (purple) (PDB IDs: 6EDB and 6CT9). The activation loop at site A is highlighted in two black boxes. c Superimposed activation loops of cGAS bound with DNA (green) and RU.521 (blue). Interactions between residues and XL-3156 (yellow, d) or G150 (purple, e). f Superimposed structures of RU.521 (light green & blue), G150 (purple), and XL-3156 (yellow) in complex with h-cGASCD. Cartoon representation of h-cGASCD omitted for clarity. The orthosteric site and allosteric site are highlighted in purple and yellow, respectively.
