Extended Data Figure 5 : Molecular basis for USP7 compound specificity.

From: Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Extended Data Figure 5

a, Superposition of the USP7–FT671 complex with indicated DUBs. Shown are the isolated cartoon structures that are shown superimposed in Fig. 3a, b. USP7 apo and USP7–FT671 (top left) show an identical switching loop position, whereas the corresponding region in other apo USP structures is in a distinct conformation that resembles the USP7~Ub complex (see Fig. 3a–c). Structures displayed: USP7 apo (purple, PDB code 1NB824); USP4 apo (PDB code 2Y6E40); yUBP6 apo (PDB code 1VJV); USP8 apo (PDB code 2GFO46); USP12 apo (PDB code 5K1647); USP14 apo (PDB code 2AYN48). b, Binding site detail, showing the interactions between palm subdomain Tyr residues (Tyr465 and Tyr514 in USP7) and the thumb subdomain and switching loop backbone present in all USP apo structures. The USP7 apo switching loop conformation disallows the Tyr465 interaction, which rotates away from the thumb subdomain, and allows Tyr514 to adopt a buried conformation (Tyr514 ‘down’ position). This generates space for compound binding. In other USP apo structures, the equivalent Tyr residues form hydrogen bonds with the thumb subdomain and occupy the compound binding site.