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Expanding the Druggable Space of the LSD1/CoREST Epigenetic Target: New Potential Binding Regions for Drug-Like Molecules, Peptides, Protein Partners, and Chromatin

Figure 1

Comparison of LSD1/CoREST X-ray structure and heterogeneous conformations from conformational clustering of molecular dynamics trajectories.

Left column: X-ray structure of LSD1/CoREST bound to the H3-histone N-terminal tail (PDB ID: 2V1D); LSD1 (orange cartoons), CoREST (cyan cartoons), H3-tail (purple spheres), and the FAD cofactor (green tubes) are highlighted. LSD1/CoREST has a well-characterized amine oxidase domain (AOD) that binds the H3-histone N-terminal tail and demethylates the fourth lysine residues of the H3-histone N-terminal tail. Connected to the AOD is the SWIRM domain crucial for substrate recognition [26]. A unique feature of LSD1 is the Tower domain that serves as interface for associating with CoREST, and is required for nucleosome binding. Middle column: MD centroids of the reduced unbound conformational ensemble. Right column: MD centroids of the reduced H3-histone N-terminal tail-bound conformational ensemble. MD centroids are color coded from red (high centroid rank) to blue (low centroid rank).

Figure 1