Expanding the Druggable Space of the LSD1/CoREST Epigenetic Target: New Potential Binding Regions for Drug-Like Molecules, Peptides, Protein Partners, and Chromatin
Panel A: SiteMap surfaces from H3-bound MD centroids are mapped onto the structure of LSD1/CoREST bound to Pro-Leu-Ser-Phe-Leu-Val peptide (purple spheres: PDB code 3ZMV). DSV Visualize was used to map the SiteMap sites from MD bound centroids onto 3ZMV with SiteMap surfaces colored according to centroid rank. The close-up views show SiteMap sites overlapping with the bound peptide. Panel B: Residues Arg312 and Phe320 are key for Pro-Leu-Ser-Phe-Leu-Val peptide binding and SiteMap predictions. Left: The X-ray conformation of Arg312 and Phe320 (Figure 6); SiteMap failed to predict a hot spot in this region after removal of the peptide coordinates. Middle: Instead, Arg312 and Phe320 adopted conformations that opened the Pro-Leu-Ser-Phe-Leu-Val binding pocket leading to SiteMap predictions of a clear hot spot. Right: MD snapshots in which residues Arg312 and Phe320 adopted conformations that closed binding site and prevented the prediction of SiteMap hot spots in the Pro-Leu-Ser-Phe-Leu-Val binding site.